U.S. patent number 4,308,382 [Application Number 06/121,836] was granted by the patent office on 1981-12-29 for 4-[[3-[.alpha.-aminobenzyl]phenyl]methyl]morpholine and 4-[-[3-benzoylphenyl]ethyl]morpholine.
This patent grant is currently assigned to Sterling Drug Inc.. Invention is credited to Bernard L. Zenitz.
United States Patent |
4,308,382 |
Zenitz |
December 29, 1981 |
**Please see images for:
( Certificate of Correction ) ** |
4-[[3-[.alpha.-Aminobenzyl]phenyl]methyl]morpholine and
4-[-[3-benzoylphenyl]ethyl]morpholine
Abstract
N-{2, 3- and 4-[R.sub.1
-(phenyl)-C(=X)]-phenyl-lower-alkyl}amines, useful as
anti-inflammatory agents, are prepared either by reduction of 2-,
3- or 4-[R.sub.1 -(phenyl)-CO]-phenyl-lower-alkanoylamines, which
are also useful as anti-inflammatory agents; by benzoylating a
phenyl-lower-alkylamine; by reaction of a 2-, 3- or
4-lithiophenyl-lower-alkylamine with a R.sub.1
-(phenyl)-carboxaldehyde, a R.sub.1 -(phenyl)-lower-alkyl ketone or
a R.sub.1 -(phenyl)-carbonitrile; by reaction of a 2-, 3- or
4-[R.sub.1 -(phenyl)-CO]-phenyl-lower-alkyl tosylate with an
appropriate amine; or by transformations involving manipulations of
a carbonyl or carbinol group.
Inventors: |
Zenitz; Bernard L. (Rensselaer,
NY) |
Assignee: |
Sterling Drug Inc. (New York,
NY)
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Family
ID: |
26819863 |
Appl.
No.: |
06/121,836 |
Filed: |
February 15, 1980 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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72067 |
Sep 4, 1979 |
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902569 |
May 3, 1978 |
4216326 |
Aug 5, 1980 |
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813167 |
Jul 5, 1977 |
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641511 |
Dec 17, 1975 |
4069256 |
Jan 17, 1978 |
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542553 |
Jan 20, 1975 |
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Current U.S.
Class: |
544/162;
544/175 |
Current CPC
Class: |
C07D
207/06 (20130101); C07D 207/20 (20130101); C07D
211/12 (20130101); C07D 211/14 (20130101); C07D
211/16 (20130101); C07D 213/16 (20130101); C07D
309/12 (20130101); C07D 265/30 (20130101); C07D
279/12 (20130101); C07D 295/096 (20130101); C07D
295/112 (20130101); C07D 295/135 (20130101); C07D
223/04 (20130101) |
Current International
Class: |
C07D
207/00 (20060101); C07D 207/20 (20060101); C07D
207/06 (20060101); C07D 211/16 (20060101); C07D
211/14 (20060101); C07D 211/00 (20060101); C07D
211/12 (20060101); C07D 213/00 (20060101); C07D
213/16 (20060101); C07D 309/00 (20060101); C07D
309/12 (20060101); C07D 223/04 (20060101); C07D
265/00 (20060101); C07D 295/112 (20060101); C07D
295/135 (20060101); C07D 295/00 (20060101); C07D
223/00 (20060101); C07D 279/00 (20060101); C07D
265/30 (20060101); C07D 295/096 (20060101); C07D
279/12 (20060101); C07D 295/10 (); C07D
295/12 () |
Field of
Search: |
;544/391,162,175 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2601923 |
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Jul 1976 |
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DE |
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1549342 |
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Nov 1968 |
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FR |
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Primary Examiner: Sutto; Anton H.
Attorney, Agent or Firm: Webb; William G. Wyatt; B.
Woodrow
Parent Case Text
RELATED APPLICATIONS
This is a continuation-in-part of my copending application Ser. No.
72,067, filed Sept. 4, 1979, abandoned July 18, 1980, which is a
division of my copending application Ser. No. 902,569, filed May 3,
1978, now U.S. Pat. No. 4,216,326, patented Aug. 5, 1980, which in
turn is a continuation-in-part of my prior application Ser. No.
813,167, filed July 5, 1977, abandoned May 5, 1978, which in turn
is a continuation-in-part of my prior application Ser. No. 641,511,
filed Dec. 17, 1975, and now U.S. Pat. No. 4,069,256, patented Jan.
17, 1978, which in turn is a continuation-in-part of my prior
application Ser. No. 542,553, filed Jan 20, 1975, abandoned Jan.
12, 1976.
Claims
I claim:
1. A compound having the formula: ##STR41## where the group
>C.dbd.X represents >C.dbd.O and R.sub.3 represents
lower-alkyl or where the group >C.dbd.X represents
>CHNH.sub.2 and R.sub.3 represents hydrogen.
2. 4-{[3-(.alpha.-Aminobenzyl)phenyl]methyl}morpholine according to
claim 1.
3. 4-[1-(3-Benzoylphenyl)ethyl]morpholine according to claim 1.
Description
BACKGROUND OF THE INVENTION
(a) Field of the Invention
This invention relates to N-{2-, 3- and 4-[R.sub.1
-(phenyl)-C(=X)]-phenyl-lower-alkyl}amines useful as
antiinflammatory agents.
(b) Description of the Prior Art
A very large class of organic compounds of widely diverse
structural types are known to be useful as antiinflammatory agents,
but many of such anti-inflammatory agents are acidic, for example
.alpha.-(3-benzoylphenyl)propionic acid, known generically as
ketoprofen (British Pat. No. 1,164,585 published Sept. 17, 1969).
Such acidic agents are often irritating, and in some cases are
ulcerogenic, to the gastric mucosa when administered orally. There
is thus a great need for anti-inflammatory agents, for example
compounds having a basic amine function, which might be expected to
be nonirritating to the gastric mucosa. Although the chemical
literature describes numerous types of amine-substituted compounds
asserted to have anti-inflammatory activity [see for example U.S.
Pat. Nos. 3,770,748, patented Nov. 6, 1973 and 3,803,127, patented
Apr. 9, 1974 (N-phenylpolymethyleneimines); U.S. Pat. Nos.
3,772,311, patented Nov. 13, 1973 and 3,773,772, patented Nov. 20,
1973 (polymethyleneimino-lower-alkanoylpyrazoles); U.S. Pat. No.
3,773,944, patented Nov. 20, 1973 (1-[3-aminopropyl]phthalans);
U.S. Pat. No. 3,801,594, patented Apr. 2, 1974
(3-amino-lower-alkylindoles); U.S. Pat. No. 3,810,985, patented May
14, 1974 (4-anilino-1,3,5-triazines) and French Patent 1,549,342,
delivre Nov. 4, 1968 (4-[benzoylphenylmethyl]morpholines)], no such
basic compounds are known to be commercially available, and none
are known to be under advanced investigation by pharmacologists for
possible commercial development. The search for an effective,
nonacidic anti-inflammatory agent for commercial development has
therefore continued.
My U.S. Pat. No. 4,069,256, which is identified above in the
section headed RELATED APPLICATIONS, and several foreign patent
publications corresponding thereto, for example Belgian Pat. No.
837,706, granted July 20, 1976, disclose compounds having the
formula I below where R.sub.1, R.sub.2, R.sub.3, >C.dbd.X and
N.dbd.B have each of the meanings given below with respect to the
compounds of formula I except that, in the patent disclosures, the
group R.sub.8 is defined as being only lower-alkyl or cyclohexyl,
and the group corresponding to R.sub.9, in addition to the meanings
given below with respect to the compounds of formula I, is defined
as hydrogen.
SUMMARY OF THE INVENTION
In one of its composition of matter aspects, the invention relates
to certain N-{2-, 3- and 4-[R.sub.1
-(phenyl)C(.dbd.X)]-phenyl-lower-alkyl}amines:
2-, 3- and 4-[R.sub.1 -(phenyl)--C(=X)]-phenyl-CHR.sub.3 CH.sub.2
-N.dbd.B which are useful as anti-inflammatory agents, certain
species of which are also useful as analgesics.
DETAILED DESCRIPTION INCLUSIVE OF THE PREFERRED EMBODIMENTS
More specifically, the invention relates to N-{3-[R.sub.1
-(phenyl)-C(=X)]phenyl-lower-alkyl}amines, which are useful as
anti-inflammatory agents, having the formula: ##STR1## where
R.sub.1 represents hydrogen or from one to two, the same or
different, lower-alkyl, hydroxy, lower-alkoxy, trifluoromethyl,
lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or
halogen selected from fluorine, chlorine and bromine; R.sub.2
represents hydrogen, or lower-alkoxy or hydroxy in the 4-position,
or lower-alkyl in either of the 2-, 4-, 5- or 6-positions; R.sub.3
represents hydrogen or lower-alkyl; the group >C.dbd.X
represents >C.dbd.O, >C(R.sub.3)H, >C.dbd.CH.sub.2,
C.dbd.NOH or >CHN(R.sub.3).sub.2 ; and N.dbd.B represents one of
the groups ##STR2## where R.sub.4 and R.sub.5 each represent
lower-alkyl; R.sub.6 and R.sub.7 each represent hydrogen,
lower-alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl,
3-cyclohexylpropyl or benzyl; R.sub.9 represents lower-alkyl,
cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cycylhexylpropyl
or benzyl; Z represents O, S or N-R.sub.8 ; R.sub.8 represents
lower-alkyl, cycloalkyl containing from three to seven ring carbon
atoms, phenyl or phenyl-lower-alkyl; and n represents one of the
integers 1, 2 and 3.
Preferred compounds of formula I are those where R.sub.1 represents
hydrogen or from one to two, the same or different, lower-alkyl,
lower-alkoxy or halogen; R.sub.2 represents hydrogen, or
lower-alkoxy or hydroxy in the 4-position; and N.dbd.B represents
one of the groups ##STR3## in which R.sub.6 represents hydrogen,
lower-alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl or
3-cyclohexylpropyl; R.sub.7 represents hydrogen; R.sub.9 represents
cyclohexylmethyl; Z represents O or N-R.sub.8 ; R.sub.8 represents
cycloalkyl containing from three to seven ring carbon atoms, phenyl
or phenyllower-alkyl; and R.sub.3 and n have the meanings given
above.
Particularly preferred compounds of formula I within the ambit of
the preferred aspects of the invention as described above are those
where R.sub.1 represents hydrogen or from one to two, the same or
different, lower-alkoxy, lower-alkyl or halogen; R.sub.2 represents
hydrogen or lower-alkoxy or hydroxy in the 4-position; >C.dbd.X
represents >C.dbd.O, >C(R.sub.3)OH, >C(R.sub.3)H,
>C.dbd.CH.sub.2, >C.dbd.NOH or >CHNH.sub.2 ; and N.dbd.B
represents one of the groups ##STR4## in which n represents the
integers 1 or 2; and R.sub.3, R.sub.6 and R.sub.9 have the meanings
given above.
Other particularly preferred compounds within the ambit of Formula
I are those having the formula ##STR5## where R.sub.3 is
lower-alkyl.
Still other particularly preferred compounds within the ambit of
formula I are those having the formula ##STR6## where >C.dbd.X
is >C.dbd.O, >C.dbd.NOH or >CHN(R.sub.3).sub.2 ; and
R.sub.3, all occurrences, and R.sub.6 are each hydrogen or
lower-alkyl.
Still other particularly preferred compounds within the ambit of
formula I are those having the formula ##STR7## wherein R.sub.3 is
hydrogen or lower-alkyl; and R.sub.8 is cycloalkyl containing from
three to seven ring carbon atoms, phenyl or phenyl-lower-alkyl.
Also within the purview of the present invention are compounds
having the formula: ##STR8## where the group >C.dbd.X represents
>C.dbd.O and R.sub.3 represents lower-alkyl or where the group
>C.dbd.X represents >CHNH.sub.2 and R.sub.3 represents
hydrogen.
Also within the purview of the present invention are compounds
having the formula: ##STR9## where R.sub.1 ; R.sub.2 ; R.sub.3 ;
and C.dbd.X have the meanings given above; the R.sub.1
-(Phenyl)-(C.dbd.X)- group can be attached to either the 2-, 3- or
4-position of the benzene ring of the R.sub.2 -(Phenyl)CR.sub.3
R.sub.3 'CH.sub.2 -N.dbd.B moiety; the R.sub.2 substituent can be
attached to any position of the benzene ring of the latter group
which is not occupied by the R.sub.1 -(Phenyl)-C(.dbd.X)- group,
i.e. the 2-, 3-, 4-, 5- or 6-position; R.sub.3 ' represents
hydrogen or lower-alkyl; and N.dbd.B, in addition to the meanings
given above, also represents one of the groups ##STR10## where
R.sub.8 is hydrogen and Y and Y' each represents O or S.
Preferred compounds of formula Ib are those where R.sub.1, R.sub.2
and R.sub.8 are each hydrogen; R.sub.3 is lower-alkyl; R.sub.3 ' is
hydrogen or lower-alkyl; >C.dbd.X is >C.dbd.O; the R.sub.1
-(Phenyl)(C.dbd.X)- group is attached to either the 3- or
4-position of the benzene ring of the R.sub.2 -(Phenyl)-CR.sub.3
R.sub.3 'CH.sub.2 -N.dbd.B moiety; and N.dbd.B represents one of
the groups ##STR11## where Y and Y' are each O or S; and Z is O, S
or N-R.sub.8, where R.sub.8 is hydrogen.
As used herein, the terms lower-alkyl and loweralkoxy mean
saturated, monovalent, aliphatic radicals, including branched chain
radicals, of from one to four carbon atoms, for example methyl,
ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy and isobutoxy.
The compounds of formulas I or Ib in which the group C.dbd.X
represents >C(R.sub.3)OH where R.sub.3 is hydrogen are prepared
by reaction of an appropriate 2-, 3- or 4-[R.sub.1
-(phenyl)-CO]-phenyl-lower-alkanoyl halide of formula III (prepared
by reaction of the corresponding acid of formula II with a thionyl
halide) with an appropriate amine of formula IV, H-N.dbd.B, and
reduction of the resulting 2-, 3- or 4-[R.sub.1
-(phenyl)-CO]-phenyl-lower-alkanoylamine of formula V with a
reagent effective to reduce amides to amines, for example an alkali
metal aluminum hydride, a trialkylaluminum or a dialkylaluminum
hydride. The method is represented by the following reaction
sequence: ##STR12## where R.sub.1, R.sub.2, R.sub.3 and R.sub.3 '
have the meanings given above, Hal represents halogen, and N.dbd.B
in addition to the meanings given above also represents the group
--NHCHR.sub.3 (CH.sub.2).sub.n N(R.sub.4).sub.2 where R.sub.3,
R.sub.4 and n have the meanings given above. The preparation of the
acid halide is carried out either with or without a solvent by
heating the acid with a molar excess of the thionyl halide.
Conversion of the halide to the amide of formula V is effected by
reacting the halide with the amine in the presence of an
acid-acceptor, for example an alkali metal carbonate or
bicarbonate, a tri-lower-alkylamine or an excess of the amine,
H--N.dbd.B. The reaction is preferably carried out in an inert
organic solvent, for example methylene dichloride, benzene, toluene
or xylene. Reduction of the amide with an alkali metal aluminum
hydride is carried out in an inert organic solvent, for example
diethyl ether, tetrahydrofuran, dioxane or dibutyl ether.
The compounds corresponding to formula V having the formula
##STR13## where the group >C.dbd.X represents >CH.sub.2, and
R.sub.1 R.sub.2, R.sub.3, R.sub.3 ' and N.dbd.B have the meanings
given above, are also within the purview of the invention. The
latter compounds are prepared from the corresponding compounds
where >C.dbd.X represents >C.dbd.O by catalytic reduction of
the latter over a palladium-on-charcoal catalyst at a hydrogen
pressure around 50-60 p.s.i.
Preferred compounds within the ambit of formula V and Va are those
where R.sub.1 and R.sub.2 each represent hydrogen; R.sub.3 '
represents hydrogen; N.dbd.B represents one of the groups ##STR14##
where R.sub.6 represents lower-alkyl or cyclohexylmethyl; R.sub.9
represents cyclohexylmethyl; Z represents O or N-R.sub.8 ; R.sub.8
represents cycloalkyl containing from three to seven ring carbon
atoms, phenyl or phenyl-lower-alkyl; n represents the integer 2;
and R.sub.3 and R.sub.4 have the meanings given above.
Particularly preferred compounds of formulas V and Va within the
ambit of the preferred species described above are those having the
formulas ##STR15## where >C.dbd.X is >C.dbd.O or
>CH.sub.2. As indicated by the above reaction, reduction of the
2-, 3- and 4-[R.sub.1 -(phenyl)-CO]-phenyl-lower-alkanoylamines of
formula V also effects reduction of the carbonyl group of the
R.sub.1 -(phenyl)-CO moiety to the carbinol group, CHOH. This
reduction can be avoided if desired by protecting the carbonyl
group of the R.sub.1 -(phenyl)-CO moiety with a ketal group, for
example the ethylene glycol ketal. The ketals are prepared by
reaction of the carbonyl compound with an alcohol in the pressure
of an acid catalyst under dehydrating conditions. The ketal group
can then be removed by hydrolysis at a later stage after reduction
of the amide function.
Alternatively, when the carbonyl group is reduced to the carbinol
group, the carbinols can be reoxidized to the ketones if compounds
where >C.dbd.X is a carbonyl group are desired. Preferred
oxidizing agents for this purpose are chromic acid or nitric
acid/perchloric acid, and it is preferred to carry out the reaction
in an inert organic solvent, for example benzene when chromic acid
is the oxidant and 1,2-dimethoxyethane when nitric acid/perchloric
acid is the oxidant.
Another method for preparing the compounds of formulas I and Ib,
where >C.dbd.X is a carbonyl group and R.sub.2 is hydroxy or
lower-alkoxy in the 4-position, comprises acylating a
phenyl-lower-alkylamine of formula VI with a benzoic acid halide of
formula VII, R.sub.1 -(phenyl)-CO-Hal, under Friedel-Crafts
conditions as represented by the reaction: ##STR16## where R.sub.1,
R.sub.3, R.sub.3 ', N.dbd.B and Hal have the meanings given above.
The reaction is carried out by adding the amine of formula VI to a
stirred mixture of the acid chloride and a suitable Lewis acid
which serves as a Friedel-Crafts catalyst, for example an aluminum
halide or ferric chloride. A preferred catalyst is an aluminum
halide.
The compounds of formulas I and Ib where the group >C.dbd.X
represents a carbonyl group can also be prepared by reaction of a
3-benzoylphenyl-lower-alkyl p-toluenesulfonate having the formula
VIII with an amine, H--N.dbd.B, in the presence of an acid-acceptor
according to the reaction: ##STR17## where R.sub.1, R.sub.2,
R.sub.3, R.sub.3 ' and N.dbd.B have the meanings given above, and
Ts represents the p-toluenesulfonyl group. The reaction is
preferably carried out by heating the reactants in an inert organic
solvent, for example dimethylformamide (DMF) or a loweralkanol.
Suitable acid-acceptors are alkali metal carbonates or bicarbonates
or an excess of the amine, H-N.dbd.B.
The tosylates of formula VIII are in turn prepared by a sequence of
reactions involving reduction, with an alkali metal borohydride, of
a 2-, 3- or 4-bromophenyl-lower-alkanoldehyde to the corresponding
2-, 3- or 4-bromophenyl-lower-alkanol; reaction of the latter with
dihydropyran in the absence of solvent and in the presence of a few
drops of concentrated hydrochloric acid to prepare the
corresponding 2-, 3- or 4-bromophenyl-lower-alkane
tetrahydropyranyl ether; reaction of the latter with butyl lithium
followed by an appropriate R.sub.1 -(phenyl)-nitrile and hydrolysis
of the tetrahydropyranyl ether group; and reaction of the resulting
2-, 3- or 4-benzoylphenyl-lower-alkanol with p-toluenesulfonyl
chloride in the presence of pyridine. The method is represented by
the following reaction sequence: ##STR18## where R.sub.1, R.sub.2,
R.sub.3 and R.sub.3 ' have the meanings given above, and Ts
represents the p-toluenesulfonyl group.
The compounds of formulas I and Ib where the group >C.dbd.X
represents >C.dbd.O or >C(R.sub.3)OH where R.sub.3 is
hydrogen or lower-alkyl are prepared by reacting a 3- or
4-halophenyl-lower-alkylamine of formula IX with a lower-alkyl
lithium in an aprotic organic solvent, for example diethyl ether,
and reacting the resulting aryl lithium directly either with a
R.sub.1 -(phenyl)-carbonitrile, R.sub.1 -(phenyl)-CN (to prepare
the compounds where >C.dbd.X is >C.dbd.O), or with a R.sub.1
-(phenyl)-carboxaldehyde, R.sub.1 -(phenyl)-CHO (to prepare the
compounds where R.sub.3 is hydrogen), or with a R.sub.1 -(phenyl)
lower-alkyl ketone, R.sub.1 -(phenyl)-COR.sub.3 (to prepare the
compounds where R.sub.3 is lower-alkyl). During the course of the
reaction of the aryl lithium with an aldehyde, and for reasons not
completely understood, some of the carbinol product (C.dbd.X is
CHOH) is oxidized to the ketone, and in such cases it is necessary
to reduce the crude product with an alkali metal borohydride as
described hereinbelow.
The 2-, 3- and 4-halophenyl-lower-alkylamines of formula IX are in
turn prepared by one of two methods depending upon the identity of
the group N.dbd.B in the final product. The compounds of formula IX
where N.dbd.B is a secondary amino group are prepared by reaction
of the corresponding primary amine with a 3- or
4-halophenyl-lower-alkanol of formula X, followed by reduction of
the resulting Schiff base with an alkali metak borohydride. The
compounds of formula IX where N.dbd.B is a tertiary amino group are
prepared by reaction of a 2-, 3- or 4-halophenyl-lower-alkanal of
formula X with a secondary amine, conversion of the resulting 2-,
3- or 4-halophenylvinylamine of formula XI to the iminium salt
having the formula XII by reaction of the former with mineral acid,
and reduction of the iminium salt with an alkali metal metal
borohydride. The condensation of the aldehyde with the amine in the
latter procedure is preferably carried out in a water immiscible
solvent, for example, benzene, toluene or xylene, at the reflux
temperature thereof under a water separator which is used to
collect the water as it is produced in the reaction. The reduction
if the iminium salt with an alkali metal borohydride is carried out
in an inert organic solvent, for example a lower-alkanol or
dimethylformamide (DMF). The overall method is represented by the
reaction sequence: ##STR19## where R.sub.1, R.sub.2, R.sub.3,
R.sub.3 ', N.dbd.B and Hal have the meanings given above, and
X.sup..crclbar. represents an anion of a mineral acid.
The methods described above are used to prepare the compounds of
formulas I or Ib where >C.dbd.X is either a carbonyl group,
>C.dbd.O, or a carbinol group, >C(R.sub.3)OH, where R.sub.3
is either hydrogen or lower-alkyl. The compounds of formulas I or
Ib where the group >C.dbd.X has the other meanings given are
prepared by simple chemical transformations involving the carbonyl
or carbinol groups. Thus the compounds where the group >C.dbd.X
represents >C(R.sub.3)H, where R.sub.3 is either hydrogen or
lower-alkyl, are prepared by catalytic reduction with hydrogen of
the corresponding carbinol, >C(R.sub.3)OH, in the presence of
perchloric acid. A preferred catalyst is palladium-on-charcoal, and
it is preferred to carry out the reaction in glacial acetic acid as
solvent. Reduction is carried out at a pressure in the rnage from
40-100 p.s.i.
The compounds of formulas I or Ib where >C.dbd.X is the group
>C.dbd.CH.sub.2 are prepared by dehydrationa of the methyl
carbinols, where >C.dbd.X is the group ##STR20## with
concentrated sulfuric acid. The reaction is carried out by
refluxing a solution of the carbinol and sulfuric acid in a
lower-alkanol solvent.
The compounds of formulas I or Ib where >C.dbd.X is the group
>C.dbd.NOH are prepared from the corresponding ketones
(>C.dbd.X is >C.dbd.O) by heating the latter with
hydroxylamine in an inert organic solvent, for example a
lower-alkanol.
The compounds of formulas I or Ib where >C.dbd.X is the group
CHNH.sub.2 are prepared by reducing the corresponding oximes
(>C.dbd.X is >C.dbd.NOH) with sodium in a lower-alkanol. The
compounds of formulas I or Ib where >C.dbd.X is C.dbd.NOH, apart
from their usefulness as pharmaceutically active compounds as
described below, are thus also useful as intermediates for
preparation of the compounds where >C.dbd.X is
>CHNH.sub.2.
The compounds of formulas I or Ib in which >C.dbd.X represents
>CHN(CH.sub.3).sub.2 are prepared from the corresponding primary
amines by treatment of the latter with formaldehyde in the presence
of formic acid.
The compounds of formula Ia where >C.dbd.X represents
>C.dbd.O are prepared by reaction of a
3-(phenyl-CO)-phenyl-CHR.sub.3 halide of formula XIII with
morpholine according to the reaction: ##STR21## where R.sub.3 and
Hal have the meanings given above. The reaction is carried out by
reacting a solution of the halide with a molar excess of morpholine
at ambient temperature in an inert organic solvent, for example
methanol, ethanol, isopropanol or DMF. A preferred solvent is
DMF.
The compounds of formula Ia where the group >C.dbd.X represents
>CHNH.sub.2 are prepared from the corresponding compounds where
>C.dbd.X represents >C.dbd.O by conversion of the latter to
the oxime and reduction of the latter to the amine as described
above.
The 2-, 3- and 4-[R.sub.1 -(phenyl)-C.dbd.X]-phenyl-CR.sub.3
R.sub.3 'CO-N.dbd.B compounds of formula V where C.dbd.X is
C(R.sub.3)H, where R.sub.3 is hydrogen, are prepared by catalytic
reduction of the corresponding compounds of formula V where C.dbd.X
is C.dbd.O with hydrogen over a palladium-on-charcoal catalyst
which catalyzes reduction of the ketone carbonyl group without
reduction of the amide carbonyl group. The reduction is carried out
at a pressure in the range from 35-90 p.s.i. and at a temperature
from 20.degree.-60.degree. C. and in an inert organic solvent, for
example a lower-alkanol such as methanol, ethanol or
isopropanol.
The amines of formula IV where -N.dbd.B is the group: ##STR22##
where R.sub.8 is hydrogen, lower-alkyl, cycloalkyl, phenyl or
phenyl-lower-alkyl are known compounds.
The amines in which -N.dbd.B is the group: ##STR23## where n is 2
are also known, having been generally described in U.S. Pat. No.
3,238,215. As described therein, they are prepared by catalytic
reduction over platinum oxide of appropriate R.sub.3, R.sub.6 or
R.sub.7 -substituted pyridines, which are commercially
available.
The amines where N.dbd.B is the group: ##STR24## where n is the
integer and R.sub.7 is hydrogen are prepared by refluxing a mixture
of an appropriate alkanedione, ammonium acetate and glacial acetic
acid, and catalytic reduction over platinum oxide of the resulting
2-R.sub.3 -5-R.sub.6 -pyrrole according to the reaction sequence:
##STR25## where R.sub.3 and R.sub.6 have the meanings given
above.
Alternatively, the amines in which -N.dbd.B is the group: ##STR26##
where n is 1 and R.sub.7 is hydrogen are prepared by reaction of a
Grignard reagent, R.sub.6 MgHal, with a 4-R.sub.3
-4-halobutyronitrile, R.sub.3 --CH--(Hal)--(CH.sub.2).sub.2 --CN;
direct cyclization of the resulting 1-amino-1-R.sub.6 -4-R.sub.3
-4-halobutene; and catalytic reduction of the resulting 2-R.sub.6
-5-R.sub.3 -4,5-dihydropyrrole as indicated by the reaction
sequence: ##STR27## where R.sub.3, R.sub.6 and Hal having the
meanings given above.
The amines where --N.dbd.B is the group: ##STR28## are
advantageously prepared, like the amines where --N.dbd.B is the
group: ##STR29## where n is 2, by catalytic reduction over platinum
oxide of the corresponding 4-R.sub.9 -pyridine.
The amines where --N.dbd.B is the group: ##STR30## where R.sub.3
and R.sub.7 are hydrogen, n is the integer 3, and R.sub.6 has the
meanings given above are prepared by Beckmann rearrangement of an
appropriate R.sub.6 -substituted-cyclohexanone oxime and reduction,
with lithium aluminum hydride, of the resulting lactam according to
the reaction: ##STR31##
The amines of formula VI where --N.dbd.B is the group: ##STR32##
where Z is 0 are prepared according to the method described in
British Patent 835,717 which comprises passing a vaporized mixture
of a glycol ether having the formula ##STR33## together with
ammonia and hydrogen over a hydrogenation/dehydrogenation catalyst
based on either nickel or cobalt at a temperature from 150.degree.
to 250.degree. C. A preferred catalyst is nickel on kieselguhr.
The amines of formula IV in which --N.dbd.B is the group: ##STR34##
where Z is S are preferably prepared by the methods described by
Idson et al., J. Am. Chem. Soc. 76, 2902 (1954) which involves
either the reaction of sodium sulfide with an appropriate
bis-2-haloethylamine: ##STR35## or the reaction of ammonia with an
appropriate bis-2-haloethyl sulfide: ##STR36## where R.sub.3 and
R.sub.6 have the meanings given above, and Hal represents
halogen.
The amines of formula IV in which N.dbd.B is the group: ##STR37##
where Y and Y' represent O or S are prepared by reaction of
commercially available 4,4-dihydroxypiperidine with either ethylene
glycol, 2-mercaptoethanol or 1,2-ethanedithiol (to prepare the
respective compounds where Y and Y' are both O, or Y is O and Y' is
S, or Y and Y' are both S). The reaction is carried out by
refluxing a solution of the reactants in the presence of a
catalytic amount of a non-volatile strong acid, for example
p-toluenesulfonic acid, in a water immiscible organic solvent, for
example benzene, toluene or xylene, under a Dean-Stark trap until
no further water is produced in the reaction and collected in the
trap.
The 2-, 3- and R.sub.4 -[R.sub.1
-(phenyl)-CO]-phenyl-lower-alkanoic acids of formula II where
R.sub.2 is hydrogen or lower-alkyl are generally known compounds
prepared by the methods described in British Pat. No. 1,164,585.
Although the compounds of formula II where R.sub.2 is hydroxy can
also be prepared by the methods used to prepare the compounds where
R.sub.2 is hydrogen or lower-alkyl and the compounds of formula II
so-prepared converted, as described above, to the final products of
formulas I or Ib, it is preferred to prepare the compounds of
formulas I or Ib where R.sub.2 is hydroxy from a
4-lower-alkoxy-phenyl-lower-alkanoic acid by conversion of the
latter to the corresponding acid halide; conversion of the latter
to the corresponding 4-lower-alkoxyphenyl-lower-alkanoyl-amine by
reaction of the acid halide with an amine, H--N.dbd.B, and
reduction of the resulting amide with a reagent effective to reduce
amines to amines, for example an alkali metal aluminum hydride;
reaction of the resulting amine with an acid halide, R.sub.1
-(phenyl)-CO-Hal, using Friedal-Crafts conditions; and finally
cleavage of the lower-alkoxy group to the hydroxy group, using
well-known methods such as heating with hydrobromic acid. The
method for the preparation of the N-{3-[R.sub.1
-(phenyl)-CO]-phenyl-lower-alkyl} amine is represented by the
following reaction sequence: ##STR38## where R.sub.1, R.sub.3,
R.sub.3 ', R.sub.4, N.dbd.B and Hal have the meanings given above.
The reaction conditions for the first four reactions in this
reaction sequence have been described above, and cleavage of the
ether with hydrobromic acid is a conventional reaction well known
to the organic chemist.
The 2-, 3- and 4-halophenyl-lower-alkanals of formula X where
R.sub.3 ' is hydrogen are prepared via the Darzens glycidic ester
condensation by reaction of a 2-, 3- or 4-halo-lower-alkanophenone
with a lower-alkyl haloacetate in the presence of an alkali metal
alkoxide and saponification and decarboxylation of the resulting
glycidic ester. The method is represented by the following reaction
sequence: ##STR39##
The novel compounds of the instant invention are the compounds of
formulas I, Ia and V and the acid-addition salts of the compounds
of formulas I, Ia, Ib and V which contain a basic amine group
capable of salt formation with acids, i.e. the compounds of formula
V where N.dbd.B is the group ##STR40## where Z is N-R.sub.8. The
compounds of formulas I, Ia, Ib and V in free base form are
converted to the acid-addition salt form by interaction of the base
with an acid. In like manner, the free base can be regenerated from
the acid-addition salt form in the conventional manner, that is by
treating the salts with cold, weak aqueous bases, for example
alkali metal carbonates and alkali metal bicarbonates. The bases
thus regenerated can then be interacted with the same or a
different acid to give back the same or a different acid-addition
salt. Thus the novel bases and all of their acid-addition salts are
readily interconvertible.
It will thus be appreciated that formulas I, Ia, Ib and V not only
represent the structural configuration of the bases of formulas I,
Ia, Ib and V but are also representative of the structural entities
which are common to all of the compounds of formulas I, Ia, Ib and
V, whether in the form of the free base or in the form of the
acid-addition salts of the base. It has been found that by virtue
of these common structural entities, the bases and their
acid-addition salts have inherent pharmacological activity of a
type to be more fully described hereinbelow. This inherent
pharmacological activity can be enjoyed in useful form for
pharmaceutical purposes by employing the free bases themselves or
the acid-addition salts formed from pharmaceutically-acceptable
acids, that is acids whose anions are innocuous to the animal
organism in effective doses of the salts so that beneficial
properties inherent in the common structural entity represented by
the free bases is not vitiated by side effects ascribable to the
anions.
In utilizing this pharmacological activity of the salts of the
invention, it is preferred, of course, to use pharmaceutically
acceptable salts. Although water-insolubility, high toxicity, or
lack of crystalline character may make some particular salt species
unsuitable or less desirable for use as such in a given
pharmaceutical application, the water-insoluble or toxic salts can
be converted to the corresponding pharmaceutically-acceptable bases
by decomposition of the salt with aqueous base as explained above,
or alternatively they can be converted to any desired
pharmaceutically-acceptable acid-addition salt by double
decomposition reactions involving the anion, for example by
ion-exchange procedures.
Moreover, apart from their usefulness in pharmaceutical
applications, the salts are useful as characterizing or identifying
derivatives of the free bases or in isolation or purification
procedures. Like all of the acid-addition salts, such
characterizing or purification salt derivatives can, if desired, be
used to regenerate the pharmaceutically-acceptable free bases by
reaction of the salts with aqueous base, or alternatively can be
converted to a pharmaceutically-acceptable acid-addition salt by,
for example, ion-exchange procedures.
It will be appreciated from the foregoing that all of the
acid-addition salts of the new bases are useful and valuable
compounds, regardless of considerations of solubility, toxicity,
physical form and the like, and are accordingly within the purview
of the instant invention.
The novel feature of the compounds of the invention, then, resides
in the concept of the bases and cationic forms of the new N-{2-, 3-
and 4- [R.sub.1 -(phenyl)-C(.dbd.X)]-phenyl-lower-alkyl}amines and
not in any particular acid moiety or acid anion associated with the
salt forms of the compounds; rather, the acid moieties or anions
which can be associated with the salt forms are in themselves
neither novel nor critical and therefore can be any acid anion or
acid-like substance capable of salt formation with the bases. In
fact, in aqueous solutions, the base form or water-soluble
acid-addition salt form of the compounds of the invention both
possess a common protonated cation or ammonium ion.
Thus appropriate acid-addition salts are those derived from such
diverse acids as formic acid, acetic acid, isobutyric acid,
alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic
acid, succinamic acid, tartaric acid, citric acid, lactic acid,
benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic
acid, 1-naphthalenecarboxylic acid, cinnamic acid,
cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic
acid, acetylenedicarboxylic acid, sorbic acid, 2-furancarboxylic
acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic
acid, 3-indoleacetic acid, quinic acid, sulfamic acid,
methanesulfonic acid, isethionic acid, benzenesulfonic acid,
p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid,
diethylphosphonic acid, p-aminophenylarsinic acid, phenylstibnic
acid, phenylphosphinous acid, methylphosphinic acid,
phenylphosphinic acid, hydrofluoric acid, hydrochloric acid,
hydrobromic acid, hydriodic acid, perchloric acid, nitric acid,
sulfuric acid, phosphoric acid, hydrocyanic acid, phosphotungstic
acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid,
arsenic acid, picric acid, picrolonic acid, barbituric acid, boron
trifluoride, and the like.
The acid-addition salts are prepared by reacting the free base and
the acid in an organic solvent and isolating the salt directly or
by concentration of the solution.
Due to the presence of at least one and as many as four asymmetric
centers in the compounds of the invention, i.e. the carbon atom
adjacent the phenyl ring to which the R.sub.3 and R.sub.3 ' groups
are attached and the various asymmetric centers in the group
--N.dbd.B to which the groups R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7 and R.sub.9 are attached, the compounds of the invention
can exist in stereochemically isomeric forms which are all
considered to be within the purview of the invention. If desired,
the isolation or the production of a particular stereochemical form
can be accomplished by application of general principles known in
the art.
In standard pharmacological test procedures, the compounds of
formulas I, Ia, Ib, V and Va have been found to possess
anti-inflammatory activity and are useful as anti-inflammatory
agents. Certain species of formulas I and Ib have also been found
to possess analgesic activity and are thus useful as analgesic
agents. Moreover, certain compounds of formula I have also been
found to have antiviral activity and are thus also useful as
anti-viral agents.
Anti-inflammatory activity was determined using (1) the inhibition
of carrageenin-induced foot edema test essentially described by
Winter et al., Proc. Soc. Exp. Biol. and Med. 111, 554 (1962) as
modified by Van Arman et al., J. Pharmacol. Exptl. Therap. 150, 328
(1965) and (2) a modification of the inhibition of adjuvant-induced
arthritis test described by Pierson, J. Chronic Diseases 16, 863
(1963) and Glenn et al., Am. J. Vet. Res. 26, 1180 (1965).
The test procedures used to determine the analgesic activities of
the compounds have been described in detail in the prior art and
are as follows: the acetylcholine-induced abdominal constriction
test, which is a primary analgesic screening test designed to
measure the ability of a test agent to suppress
acetylcholine-induced abdominal constriction in mice, described by
Collier et al., Brit. J. Pharmacol. Chemotherap. 32, 295 (1968); a
modification of the antibradykinin test, which is also a primary
analgesic screening procedure, described by Berkowitz et al., J.
Pharmacol. Exp. Therap. 177, 500-508 (1971), Blane et al., J.
Pharm. Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J.
Pharmacol. 6, 312-321 (1969) and Deffenu et al., J. Pharm.
Pharmacol. 18, 135 (1966); the phenyl-p-quinone-induced writhing
test, also a primary analgesic screening test, designed to measure
the ability of a test agent to prevent phenyl-p-quinone-induced
writhing in mice, described by Pearl and Harris, J. Pharmacol.
Exptl. Therap. 154, 319-323 (1966); the rat tail flick radiant
thermal heat analgesic (agonist) test described by D'Amour and
Smith, J. Pharmacol. Exptl. Therap. 72, 74 (1941) as modified by
Bass and VanderBrook, J. Am. Pharm. Assoc. Sci. Ed. 41, 569 (1956);
and the phenazocine antagonist test, which is designed to measure
the ability of a test agent to antagonize the effect of phenazocine
in the above-indicated rat tail flick response test, described by
Harris and Pierson, J. Pharmacol. Exptl. Therap. 143, 141
(1964).
The in vitro anti-viral activity of the compounds against herpes
simplex viruses types 1 and 2 was demonstrated by the addition of
the compounds to tissue cultures infected with herpes virus.
Monolayers of tissue cultures (BSC, cell line, monkey kidney) were
infected with one hundred TCID.sub.50 (Tissue Culture Infectious
Dose.sub.50) of infectious virus. After one hour of virus
adsorption, fresh maintenance medium containing various
concentrations of the test compounds was added to the monolayers.
Cultures were then incubated at 36.degree.-37.degree. C., and after
forty-eight and seventy-two hours, cultures were examined
microscopically. In the infected control tubes as well as in those
containing inactive compounds, viral growth is indicated by the
production of characteristic cytopathic effects with the
destruction of the cells. In the presence of an active compound,
cells grow normally similar to those in the tissue culture control.
Simultaneously with the anti-viral evaluation, the toxicity of each
compound was evaluated in separate cultures. Identical
concentrations of the test compound were added to the tissue
culture monolayers in the absence of virus. Those concentrations of
the compound which show toxic effects on the cells were not
considered in the anti-viral evaluation. The activity of the
compounds was expressed in terms of the Minimal Inhibitory
Concentration (MIC), where the MIC is described as the lowest
concentration of the test compound which completely inhibits the
growth of the virus.
The compounds of the invention can be prepared for use by
incorporating them in unit dosage form as tablets or capsules for
oral administration either alone or in combination with suitable
adjuvants such as calcium carbonate, starch, lactose, talc,
magnesium stearate, gum acacia, and the like. Still further, the
compounds can be formulated for oral administration in aqueous
alcohol, glycol or oil solutions or oil-water emulsions in the same
manner as conventional medicinal substances are prepared.
The molecular structures of the compounds of the invention were
assigned on the basis of study of their infrared, ultraviolet, and
NMR spectra, and confirmed by the correspondence between calculated
and found values for elementary analyses for the elements.
The following examples will further illustrate the invention
without, however, limiting it thereto. All melting points are
uncorrected.
Preparation of Amine Intermediates
Preparation I
In three separate runs, 33.8 g. (0.20 mole) portions of
2-benzylpyridine, each in a solution of about 225 ml. of ethanol
and 22 ml. of concentrated hydrochloric acid, were reduced over 4.0
g. portions of platinum oxide catalyst under about 54 p.s.i. of
hydrogen at a temperature of about 55.degree.-61.degree. C. When
reduction was complete in each case, the catalyst was removed by
filtration, washed with small portions of ethanol, and the combined
filtrates evaporated to a volume of about 80 ml. and diluted to
approximately 500 ml. with boiling acetone. The solid which
precipitated was collected, washed with acetone and dried giving a
combined yield of 124.8 g. of 2-cyclohexylmethylpiperidine
hydrochloride, m.p. 211.degree.-213.degree. C. The free base was
regenerated from the hydrochloride by neutralization of an aqueous
solution of the latter with potassium carbonate, extraction of the
oily base into benzene, evaporation of the benzene solution to
dryness, and distillation of the residual oil in vacuo at
55.degree.-59.degree. C./0.27 mm. There was thus obtained 89.4 g.
of 2-cyclohexylmethylpiperidine.
Preparation 2
A mixture of 15.52 g. (0.10 mole) of 2-phenylpyridine, 15 ml. of
concentrated hydrochloric acid and 2.0 g. of platinum oxide in 185
ml. of ethanol in a pressure bottle was heated and shaken in a Parr
hydrogenator under 55 p.s.i. of hydrogen at a temperature around
60.degree. C. When reduction was complete in about eight hours, the
catalyst was removed by filtration and the filtrate concentrated to
about 50 ml. and diluted with 200 ml. of acetone. The solid which
separated was collected and dried to give 14.54 g. of
2-cyclohexylpiperidine hydrochloride, m.p. 251.degree.-253.degree.
C.
Preparation 3
A mixture of 9.1 g. (0.05 mole) of 2-stilbazole (Shaw et al., J.
Chem. Soc. 1933, 77-79) and 1.0 g. of platinum oxide in a solution
of 240 ml. of ethanol and 10 ml. of concentrated hydrochloric acid
in a pressure bottle was heated and shaken on a Parr hydrogenator
under about 55 p.s.i. of hydrogen at a temperature of about
60.degree. C. When reduction was complete in about eight hours, the
catalyst was removed by filtration, the filtrate concentrated to a
volume of about 50 ml. and diluted with about 200 ml. of acetone.
The solid which separated was collected and dried to give 9.6 g. of
2-(2-cyclohexylethyl)piperidine hydrochloride, m.p.
155.degree.-156.degree. C.
Preparation 4
A solution of 78.1 g. (0.84 mole) of 4-methylpyridine and 89.0 g.
(0.84 mole) of benzaldehyde in 103 g. of acetic anhydride was
heated with stirring under reflux for twenty-four hours. The
mixture was then concentrated to a thick oil in vacuo and the
residue dissolved in hot ethanol. The solid which separated was
collected and recrystallized from ethanol to give 57.9 g. of
4-styrylpyridine, m.p. 131.5.degree.-133.degree. C.
The latter (36.2 g., 0.2 mole), dissolved in 220 ml. of absolute
ethanol and 30 ml. of concentrated hydrochloric acid, was reduced
over 3.0 g. of platinum oxide under a hydrogen pressure of about 55
p.s.i. The product was worked up in the manner described above in
Preparation 1 and isolated in the form of the hydrochloride salt to
give 43.5 g. of 4-(2-cyclohexylethyl)piperidine hydrochloride, m.p.
246.degree.-248.degree. C.
Preparation 5
4-Phenylpyridine (15.5 g., 0.1 mole) dissolved in 185 ml. of
absolute ethanol and 15 ml. of concentrated hydrochloric acid was
reduced with hydrogen over 2 g. of platinum oxide under a hydrogen
pressure of about 55 p.s.i. The product was worked up in the manner
described above in Preparation 1 and isolated in the form of the
hydrochloride salt to give 15.3 g. of 4-cyclohexylpiperidine
hydrochloride. (The free base gives m.p. 106.degree.-109.degree.
C.).
Preparation 6
To a mixture of 8.6 g. (0.36 mole) of magnesium turnings in 150 ml.
of dry ether was added in small portions with cooling and stirring
a solution of 45.0 g. (0.36 mole) of benzyl chloride in 75 ml. of
anhydrous ether. When addition was complete, the mixture was
stirred for about one hour and then treated dropwise with a
solution of 26.6 g. of 4-chlorobutyronitrile in 95 ml. of ether.
When addition was complete, the ether was gradually distilled off
while replacing with an equal volume of toluene. The mixture was
heated under reflux (at about 109.degree. C.) for about thirty
minutes, cooled to about 15.degree. C., treated dropwise with 300
ml. of 10% aqueous ammonium chloride, filtered and the organic
layer separated. The latter was washed with three 100 ml. portions
of dilute hydrochloric acid, and the combined acid extracts were
basified with solid potassium carbonate. Extraction of the mixture
with ether and removal of the solvent from the combined organic
extracts afforded an oil which was distilled in vacuo to give 13.05
g. of 2-benzyl-4,5-dihydropyrrole, b.p. 123.degree.-125.degree.
C./13 mm., n.sub.D.sup.25 1.5405.
The latter, dissolved in 210 ml. of ethanol and 15 ml. of
concentrated hydrochloric acid was reduced with hydrogen over 2 g.
of platinum oxide under a hydrogen pressure of about 50 p.s.i. The
mixture was worked up in the manner described above in Preparation
1 and the product isolated in the form of the hydrochloride salt to
give 16.8 g. of 2-cyclohexylmethylpyrrolidine hydrochloride, m.p.
130.5.degree.-131.5.degree. C. (from acetone).
Preparation 7
To a suspension of 11.2 g. (1.6 mole) of lithium wire in 600 ml. of
anhydrous ether was added dropwise 125.6 g. (0.8 mole) of
bromobenzene. When addition was complete, the mixture was stirred
for about a half hour and then treated dropwise first with a
solution of 74.4 g. (0.8 mole) of picoline in 100 ml. of anhydrous
ether and then, after stirring for fifteen minutes, with a solution
of 74.0 g. (0.4 mole) of 2-phenylethyl bromide in 100 ml. of ether.
The mixture was stirred at ambient temperature for about twelve
hours and then poured with stirring onto 300 g. of ice. When all
excess lithium had reacted, the layers were separated, the aqueous
layer washed with additional ether, and the combined organic
portions were washed with brine, dried and taken to dryness to give
a residual oil which was distilled in vacuo to give 41.3 g. of
2-(3-phenylpropyl)pyridine, b.p. 76.degree.-78.degree. C./0.05 mm.,
n.sub.D.sup.25 1.5592.
The latter (19.7 g., 0.1 mole) dissolved in 235 ml. of ethanol and
15 ml. of concentrated hydrochloric acid was reduced with hydrogen
over 2 g. of platinum oxide under a hydrogen pressure of around 55
p.s.i. at about 65.degree. C. The product was worked up in the
manner described above in Preparation 1 and isolated in the form of
the hydrochloride salt to give 22.2 g. of
2-(3-cyclohexylpropyl)piperidine hydrochloride, m.p.
175.degree.-176.5.degree. C. (from ethyl acetate).
Preparation 8
Catalytic reduction of 3-benzylpyridine in glacial acetic acid over
a platinum oxide catalyst and isolation of the product using the
procedure described above in Preparation 1 affords
3-benzylpiperidine.
Preparation of Final Products
EXAMPLE 1
A solution of 25.4 g. (0.1 mole) of
.alpha.-(3-benzoylphenyl)propionic acid in 40 ml. of benzene was
added to 19.8 g. (0.166 mole) of thionyl chloride and the solution
refluxed for two and a half hours. The solvent was then removed in
vacuo, and the resulting oil (28 g.) consisting of
.alpha.-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml.
of diethyl ether and added with stirring over a thirty minute
period to a solution of 2-cyclohexylmethylpiperidine in 80 ml. of
diethyl ether. The mixture was stirred for about forty-eight hours
at ambient temperature, then filtered, the filter washed with
ether, and the combined filtrate washed once with dilute acid, once
with brine, once with aqueous potassium bicarbonate and evaporated
to dryness to give 48.2 g. of
2-cyclohexylmethyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperidine
as a pale amber glass.
The latter (35.5 g., 0.085 mole) was dissolved in 200 ml. of
diethyl ether and the solution added dropwise with stirring to a
mixture of 8.08 g. (0.21 mole) of lithium aluminum hydride in 200
ml. of ether while maintaining the temperature at
10.degree.-15.degree. C. The reaction mixture was stirred at
ambient temperature for three and one half hours, decomposed by the
dropwise addition of 8.1 ml. of water, followed by 8.1 ml. of 15%
sodium hydroxide and an additional 22.2 ml. of water. The mixture
was then stirred for one hour, filtered, and the filtrate
evaporated to dryness to give 34.0 g. of an oil, 10.5 g. of which
was chromatographed over 200 g. of alumina and eluted with a
solution of 60% hexane/40% ether. The early fractions were removed
and evaporated to dryness to give 8.0 g. of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine
as a viscous oil.
Anal. Calcd. for C.sub.28 H.sub.39 NO: C,82.91; H,9.69; N,3.45.
Found: C,83.12; H,9.80; N,3.49.
EXAMPLES 1A-1D
Following a procedure similar to that described in Example 1, the
following compounds of formula I were similarly prepared:
EXAMPLE 1A
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]ethyl}piperidine,
m.p. 122.degree.-124.degree. C. (5.8 g. from benzene/hexane)
prepared by reaction of 42 g. (0.16 mole) of 3-benzoylphenylacetyl
chloride (German Patent Appln. 2,243,444, published Mar. 8, 1944)
with 31.7 g. (0.175 mole) of 2-cyclohexylmethylpiperidine in 150
ml. of ether in the presence of 19.4 g. (0.192 mole) of
triethylamine and reduction of the resulting
2-cyclohexylmethyl-1-[(3-benzoylphenyl)acetyl]piperidine (46 g.)
with 13 g. (0.35 mole) of lithium aluminum hydride in 325 ml. of
ether.
Anal. Calcd. for C.sub.27 H.sub.37 NO: C,82.81; H,9.52; N,3.58.
Found: C,83.01; H,9.54; N,3.52.
EXAMPLE 1B
2,6-Dimethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]ethyl}-piperidine,
m.p. 115.degree.-117.degree. C. (9.53 g. from benzene/hexane)
prepared by reaction of 42 g. (0.16 mole) of 3-benzoylphenylacetyl
chloride with 19.8 g. (0.175 mole) of 2,6-dimethylpiperidine in 150
ml. of ether in the presence of 19.4 g. (0.092 mole) of
triethylamine and reduction of the resulting
2,6-dimethyl-1-[(3-benzoylphenyl)acetyl]piperidine (49 g.) with
13.9 g. (0.365 mole) of lithium aluminum hydride in 300 ml. of
ether.
Anal. Calcd. for C.sub.22 H.sub.29 NO: C,81.69; H,9.04; N,4.33.
Found: C,81.83; H,9.04; N,4.32.
EXAMPLE 1C
4-[2-(3-Benzoylphenyl)ethyl]morpholine hydrochloride monohydrate,
m.p. 177.5.degree.-180.degree. C. (29.0 g. from acetone) prepared
by reaction of 46.5 g. (0.18 mole) of 3-benzoylphenylacetyl
chloride with 17.2 g. (0.198 mole) of morpholine in 225 ml. of
methylene dichloride in the presence of 21.5 g. (0.211 mole) of
triethylamine; conversion of the resulting 49 g. of
4-[(3-benzoylphenyl)acetyl]morpholine to the corresponding ethylene
glycol ketal by reaction of the former with 125 ml. of ethylene
glycol in 1250 ml. of benzene in the presence of 2.5 g. of
p-toluenesulfonic acid; and reduction of the resulting ketal (58.6
g.) with 11.8 g. (0.31 mole) of lithium aluminum hydride in 280 ml.
of ether, followed by hydrolysis of the ketal by stirring the
product at 55.degree.-60.degree. C. with 300 ml. of 1.5N
hydrochloric acid for forty-five minutes.
Anal. Calcd. for C.sub.19 H.sub.21 NO.sub.2.HCl.H.sub.2 O: C,65.23;
H,6.91; Cl,10.13. Found: C,65.38; H,6.88; Cl,10,19.
EXAMPLE 1D
N-[2-(3-Benzoylphenyl)ethyl]-N-(3-dimethylaminopropyl)amine
dihydrochloride hemi-hydrate, m.p. 194.degree.-197.degree. C. (11.1
g. of the free base obtained as a dark oil, a small amount
converted to the dihydrochloride) prepared by reaction of 46.3 g.
(0.167 mole) of 3-benzoylphenylacetyl chloride with 30.2 g. (0.3
mole) of 3-dimethylaminopropylamine in 200 ml. of methylene
chloride in the presence of 20.1 g. (0.2 mole) of triethylamine;
conversion of the resulting 9 g. of
N-[(3-benzoylphenyl)acetyl]-N-(3-dimethylaminopropyl)amine to the
corresponding ethylene glycol ketal by reaction of 15 g. of the
former with 37.5 ml. of ethylene glycol in the presence of 9.75 g.
of p-toluenesulfonic acid in 395 ml. of benzene; and reduction of
the resulting ketal (15.6 g.) with 3.2 g. (0.084 mole) of lithium
aluminum hydride in a solution of 50 ml. of dioxane and 50 ml. of
di-n-butyl ether, followed by hydrolysis of the ketal by warming it
for one hour in 200 ml. of dilute hydrochloric acid at 55.degree.
C.
Anal. Calcd. for C.sub.20 H.sub.26 N.sub.2 0.2HCl.1/2H.sub.2 O:
C,61.22; H,7.43; Cl,18.01. Found: C,61.97; H,7.48; Cl,17.70.
Following a procedure similar to that described in Example 1, the
following 3-[R.sub.1 -(phenyl)-CO]-phenyl-lower-alkanoylamines of
formula V were similarly prepared:
EXAMPLE 1E
4-Cyclohexyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride, m.p. 208.degree.-209.degree. C. (10.7 g. from
isopropanol/diethyl ether) prepared by reaction of 8.2 g. (0.03
mole) of .alpha.-(3-benzoylphenyl)propionyl chloride with 4.9 g.
(0.03 mole) of 1-cyclohexylpiperazine in 60 ml. of methylene
dichloride in the presence of 3.6 g. (0.036 mole) of triethylamine
and conversion of the crude base (11.4 g.) thus obtained to the
hydrochloride salt in ethereal hydrogen chloride.
EXAMPLE 1F
4-Phenyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine, m.p.
121.degree.-123.degree. C. (9.1 g. from benzene/hexane) prepared by
reaction of 8.2 g. (0.03 mole) of
.alpha.-(3-benzoylphenyl)propionyl chloride with 4.7 g. (0.03 mole)
of 1-phenylpiperazine in 70 ml. of methylene dichloride in the
presence of 3.6 g. (0.036 mole) of triethylamine.
EXAMPLE 1G
4-Benzyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride, m.p. 225.degree.-226.5.degree. C. (9.0 g. from
ethanol) prepared by reaction of 9.0 g. (0.033 mole) of
.alpha.-(3-benzoylphenyl)propionyl chloride with 5.3 g. (0.03 mole)
of 1-benzylpiperazine in 75 ml. of methylene dichloride in the
presence of 3.6 g. (0.036 mole) of triethylamine and conversion of
the crude base thus obtained (12.6 g.) to the hydrochloride
salt.
EXAMPLE 1H
4-Cylohexyl-1-[(3-benzoylphenyl)acetyl]piperazine, m.p.
107.degree.-109.degree. C. (6.1 g. from hexane) prepared by
reaction of 8.5 g. (0.033 mole) of (3-benzoylphenyl)acetyl chloride
with 5.0 g. (0.03 mole) of 1-cylohexylpiperazine in 75 ml. of
methylene dichloride in the presence of 3.6 g. (0.036 mole) of
triethylamine.
EXAMPLE 1J
4-Cyclopentyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride, m.p. 178.degree.-179.degree. C. (10.3 g. from
acetone/diethyl ether) prepared by reaction of 9.0 g. (0.033 mole)
of .alpha.-(3-benzoylphenyl)propionyl chloride with 4.6 g. (0.03
mole) of 1-cyclopentylpiperazine in 100 ml. of methylene dichloride
in the presence of 3.6 g. (0.036 mole) of triethylamine.
EXAMPLE 1K
4-Cycloheptyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride, m.p. 201.degree.-204.degree. C. (10.0 g. from
acetone/diethyl ether) prepared by reaction of 9.0 g. (0.033 mole)
of .alpha.-(3-benzoylphenyl)propionyl chloride with 5.5 g. (0.03
mole) of 1-cycloheptylpiperazine in 100 ml. of methylene dichloride
in the presence of 3.6 g. (0.036 mole) of triethylamine and
conversion of the crude base thus obtained (12.5 g.) to the
hydrochloride salt.
EXAMPLE 1L
4-Cyclohexylmethyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperidine,
a viscous pale amber glass, prepared by reaction of 6.3 g. (0.02
mole) of .alpha.-(3-benzoylphenyl)propionyl chloride with 3.81 g.
(0.02 mole) of 4-cyclohexylmethylpiperidine in 75 ml. of methylene
dichloride in the presence of 2.57 g. (0.025 mole) of
triethylamine.
EXAMPLE 1M
4-Cycloheptyl-1-[(3-benzoylphenyl)acetyl]piperazine hydrochloride,
m.p. 231.degree.-233.degree. C. (2.77 g. from acetone) prepared by
reaction of 7.0 g. (0.026 mole) of (3-benzoylphenyl)acetyl chloride
with 4.1 g. (0.023 mole) of 1-cycloheptylpiperazine in 55 ml. of
methylene dichloride in the presence of 2.78 g. (0.028 mole) of
triethylamine.
EXAMPLE 2
Following a procedure similar to that described in Example 1,
2,6-dimethyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperidine (14.3
g. as an oil) was prepared from 12.7 g. of
.alpha.-(3-benzoylphenyl)propionic acid, 10 g. (0.084 mole) of
thionyl chloride, 6.22 g. (0.055 mole) of 2,6-dimethylpiperidine
and 6.05 g. (0.06 mole) of triethylamine, and the resulting amide
(14.3 g.) reduced with 3.9 g. (0.103 mole) of lithium aluminum
hydride in diethyl ether to give 13.2 g. of
2,6-dimethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine
as a yellow oil.
Anal. Calcd. for C.sub.23 H.sub.31 NO: C,82.34; H,8.71; N,4.18.
Found: C,82,22, H,8.82; N,4.15.
EXAMPLES 2A-D
Following a procedure similar to that described in Example 1, the
following compounds of formula I are similarly prepared:
EXAMPLE 2A
N-t-Butyl-N-{2-[3-(.alpha.-hydroxy-4-methyl-2-chlorobenzyl)phenyl]propyl}am
ine prepared by reaction of
.alpha.-[3-(4-methyl-2-chlorobenzoyl)phenyl]propionyl chloride with
t-butylamine and reduction, with lithium aluminum hydride, of the
resulting
N-t-butyl-N-{.alpha.-[3-(4-methyl-2-chlorobenzoyl)phenyl]propion
yl}-amine;
EXAMPLE 2B
N-Benzyl-N-t-butyl-N-{2-[3-(.alpha.-hydroxy-3-trifluoromethylbenzyl)phenyl]
propyl}amine prepared by reaction of
.alpha.-[3-(3-trifluoromethylbenzoyl)phenyl]propionyl chloride with
N-benzyl-N-t-butylamine and reduction, with lithium aluminum
hydride, of the resulting
N-benzyl-N-t-butyl-N-{.alpha.-[3-(3-trifluoromethylbenzoyl)phenyl]propiony
l}amine;
EXAMPLE 2C
N,N-Di-isobutyl-N-{2-[3-(.alpha.-hydroxy-2,4-dichlorobenzyl)phenyl]propyl}a
mine prepared by reaction of
.alpha.-[3-(2,4-dichlorobenzoyl)phenyl]propionyl chloride with
N,N-di-isobutylamine and reduction, with lithium aluminum hydride,
of the resulting
N,N-di-isobutyl-N-{.alpha.-[3-(2,4-dichlorobenzoyl)phenyl]propionyl}amine;
and
EXAMPLE 2D
4-(2-Cyclohexylethyl)-1-{2-[3-(.alpha.-hydroxy-2-bromobenzyl)-4-methylpheny
l]propyl}piperidine prepared by reaction of
.alpha.-[3-(2-bromobenzoyl)-4-methylphenyl]propionyl chloride with
4-(2-cyclohexylethyl)piperidine and reduction, with lithium
aluminum hydride, of the resulting
4-(2-cyclohexylethyl)-1-{.alpha.-[3-(2-bromobenzoyl)-4-methylphenyl]propio
nyl}piperidine.
EXAMPLE 3
To 220 g. (1.65 moles) of aluminum chloride was added with vigorous
stirring over a twenty minute period 81 g. (0.67 mole) of
acetophenone. The resulting mixture was treated dropwise with
stirring over a forty minute period with 120 g. (0.8 mole) of
bromine. When addition was complete, the mixture was stirred for an
additional fifteen minutes and then extracted with four 150 ml.
portions of ether. The combined ether extracts were washed once
with water, once with 10% potassium bicarbonate, once with
saturated brine, dried over anhydrous sodium sulfate, and
evaporated to dryness to give 141 g. of an oil which was distilled
in vacuo to give 108.7 g. of 3-bromoacetophenone, b.p.
71.5.degree.-76.degree. C./0.5 mm.
To 2,200 ml. of isopropanol in a three-necked round bottom flask
flushed with nitrogen was added in pieces 60 g. (2.6 moles) of
sodium. When all the sodium had dissolved, the mixture was cooled
to about 7.degree.-8.degree. C. and treated over a period of thirty
minutes with a solution of 318 g. (1.6 moles) of
3-bromoacetophenone and 352 g. (2.88 moles) of ethyl chloroacetate.
The mixture was stirred at 7.degree.-8.degree. C. for five hours
and then at ambient temperature for about forty-eight hours,
refluxed for one hour, distilled to remove about one liter of
isopropanol, and the residue diluted with 1900 ml. of water and
1200 ml. of toluene and stirred. The layes were separated, the
aqueous layer was extracted with additional toluene, and the
combined toluene extracts were washed with saturated brine, dried,
and evaporated to dryness to give 558.8 g. of a brown liquid which
was combined with a solution of 70 g. of sodium hydroxide in 225
ml. of water and 1200 ml. of absolute ethanol and refluxed for
about twelve hours. The mixture was then taken to dryness in vacuo
to give 575.6 g. of a solid which was dissolved in water, acidified
with dilute hydrochloric acid, and the mixture extracted with
benzene. The benzene extracts were taken to dryness to give 485.4
g. of material which was steam distilled affording 272.5 g. of
.alpha.-(3-bromophenyl)propionaldehyde.
A solution of the latter with 465 g. (2.6 moles) of
2-cyclohexylmethylpiperidine in 6 liters of benzene was refluxed
under a Dean-Stark trap for about twelve hours. The solvent was
removed in vacuo giving 712.1 g. of an oil which was distilled in
vacuo to remove lower boiling impurities. There was thus obtained
as a higher boiling pot residue 357.2 g. of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)-1-propenyl]piperidine.
The latter (0.95 mole) was dissolved in 3 liters of hexane, and the
solution cooled in an ice bath and treated with 220 ml. (1.20
moles) of 4.9 N ethereal hydrogen chloride. The white gummy solid
which separated, consisting of the iminium hydrochloride, was
collected, filtered washed with fresh hexane, dissolved in 3.5
liters of dimethylformamide, and the solution treated with 72 g.
(1.9 moles) of sodium borohydride added in small amounts over a ten
minute period. The mixture was then stirred at ambiet temperature
for about an hour and a half, treated with one liter of 10% sodium
hydroxide and 6 liters of water, and then extracted with hexane.
The combined hexane extracts afforded 305.4 g. of a yellow oil
which was distilled in vacuo to give 189.6 g. of material, b.p.
143.degree.-161.degree. C./0.06 mm., which was redistilled at 0.5
mm. (b.p. 167.degree.-187.degree. C.) to give 158.5 g. of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine.
Anal. Calcd. for C.sub.21 H.sub.32 BrN: C,66.66; H,8.52; Br,21.12.
Found: C,66.71; H,8.36; Br,21.20.
A solution of the latter (37.8 g., 0.1 mole) dissolved in 80 ml. of
diethyl ether was treated dropwise with 165 ml. (0.18 mole) of a
1.08 M solution of n-butyl lithium in diethyl ether while
maintaining the temperature around 10.degree. C. When addition was
complete, the mixture was stirred for thirty minutes at about
10.degree. C., then at ambient temperature for one hour, refluxed
for about thirty minutes, cooled once again to 10.degree. C., and
treated with a solution of 25.8 g. (0.19 mole) of
4-methoxybenzaldehyde in 50 ml. of ether while maintaining the
temperature around 15.degree.-20.degree. C. The mixture was then
refluxed for twenty minutes, cooled, basified by the addition of
110 ml. of 10% sodium hydroxide and stirred for ten minutes. The
mixture was then filtered, the organic layer separated, and the
aqueous layer extracted with additional diethyl ether. The combined
organic extracts were washed with saturaed brine, dried over sodium
sulfate, and evaporated to dryness to give 55 g. of an oil which
was dissolved in 150 ml. of absolute methanol. The solution was
treated cautiously with 7 g. of sodium borohydride, stirred at
15.degree. C. for twenty minutes, carefully acidified by the
addition of 150 ml. of sulfuric acid and extracted three times with
hexane. The aqueous solution was basified with 150 ml. of 10%
sodium hydroxide, diluted with water and extracted four times with
hexane. The combined hexane extracts afforded 32 g. of an oil which
was chromatographed on 500 g. of alumina using 1.5% isopropylamine
in hexane as eluent. The first 3 liters of eluate were collected
and set aside, and the next 3.7 liters collected and evaporated to
dryness to give 20.4 g. of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methoxybenzyl)phenyl]propyl}
piperidine as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.41 NO.sub.2 : C,79.95; H,9.49;
N,3.22. Found: C,78.88; H,9.43; N, 3.07.
EXAMPLES 3A-3H
Following a procedure similar to that described in Example 3, the
following compounds of formula I are prepared:
EXAMPLE 3A
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-3-chlorobenzyl)phenyl]propyl}pi
peridine (26.8 g. as a yellow oil) prepared by reaction of 37.8 g.
(0.1 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.19
mole of n-butyl lithium and reaction of the resulting lithio
derivative with 28.0 g. (0.2 mole) of 3-chlorobenzaldehyde in about
250 ml. of diethyl ether.
Anal. Calcd. for C.sub.28 H.sub.38 ClNO: C,76.42; H,8.70; N,3.18.
Found: C,76.64; H,8.98; N,3.16.
EXAMPLE 3B
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}pyrrolidine
(5.3 g. as a tan viscous oil) prepared by reaction of 10.8 g. (0.03
mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]pyrrolidine
with 0.06 mole of n-butyl lithium and reaction of the resulting
lithio derivative with 7.0 g. (0.066 mole) of benzaldehyde.
Anal. Calcd. for C.sub.37 H.sub.37 NO: C,82.81; H,9.52; N,3.58.
Found: C,82.29; H,10.03; N,3.51.
EXAMPLE 3C
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-3,4-dichlorobenzyl)phenyl]propy
l}piperidine (12.3 g. as an oil) prepared by reaction of 37.8 g.
(0.1 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.19
mole of n-butyl lithium and reaction of the resulting lithio
derivative with 35.1 g. (0.2 mole) of 3,4-dichlorobenzaldehyde in
diethyl ether.
EXAMPLE 3D
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-2-chlorobenzyl)phenyl]propyl}pi
peridine (30.7 g. as an oil) prepared by reaction of 37.8 g. (0.1
mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine
with 0.19 mole of n-butyl lithium and reaction of the resulting
lithio derivative with 28.0 g. (0.2 mole) of 2-chlorobenzaldehyde
in diethyl ether.
EXAMPLE 3E
2-(3-Cyclohexylpropyl)-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperid
ine (5.4 g. as a viscous oil) prepared by reaction of 12.2 g. (0.03
mole) of
2-(3-cyclohexylpropyl)-1-[2-(3-bromophenyl)propyl]piperidine with
0.68 mole of n-butyl lithium and reaction of the resulting lithio
derivative with 7.0 g. (0.06 mole) of benzaldehyde in diethyl
ether.
Anal. Calcd. for C.sub.30 H.sub.43 NO: C,83.09; H,9.99; N,3.23.
Found: C,82.92; H,10.26; N,3.19.
EXAMPLE 3F
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylmercaptobenzyl)phenyl]p
ropyl}piperidine prepared by reaction of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with
n-butyl lithium and reaction of the resulting lithio derivative
with 4-methylmercaptobenzaldehyde.
EXAMPLE 3G
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylsulfinylbenzyl)phenyl]p
ropyl}piperidine prepared by reaction of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylmercaptobenzyl)phenyl]
propyl}piperidine described in Example 3F with one molar equivalent
amount of hydrogen peroxide in formic acid.
EXAMPLE 3H
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylsulfonylbenzyl)phenyl]p
ropyl}piperidine prepared by reaction of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylmercaptobenzyl)phenyl]
propyl}piperidine described in Example 3F with two molar
equivalents of hydrogen peroxide in formic acid.
EXAMPLE 4
Following a procedure similar to that described in Example 3, 18.9
g. (0.05 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was
reacted with 0.1 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with 12.3 g. (0.103
mole) of 4-methylbenzaldehyde to give 16.9 g. of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-methylbenzyl)phenyl]propyl}p
iperidine as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.41 NO: C,83.00; H,9.85; N,3.34.
Found: C,83.04; H,10.01; N,3.31.
EXAMPLE 5
Following a procedure similar to that described in Example 3 above,
18.9 g. (0.05 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was
reacted with 0.1 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with 15.5 g. (0.11
mole) of 4-chlorobenzaldehyde. The crude product was reduced with
4.5 g. (0.12 mole) of sodium borohydride in methanol to give 16.6
g. of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-chlorobenzyl)phenyl]propyl}p
iperidine as an oil.
Anal. Calcd. for C.sub.28 H.sub.38 ClNO: C,76.42; H,8.70; Cl,8.06.
Found: C,76.82; H,8.76; Cl,8.14.
Following a procedure similar to that described in Example 5, the
following compound of formula I was similarly prepared:
EXAMPLE 5A
2-Cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-2,6-dichlorobenzyl)phenyl]propy
l}piperidine (yellow oil) prepared by reaction of 18.9 g. (0.05
mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine
with 0.1 mole of butyl lithium in diethyl ether followed by 19.2 g.
(0.11 mole) of 2,6-dichlorobenzaldehyde to give 19.3 g. of
product.
Anal. Calcd. for C.sub.28 H.sub.37 Cl.sub.2 NO: C,70.87; H,7.86;
Cl,14.94. Found: C,71.06; H,8.08; Cl,14.81.
EXAMPLE 6
Following a procedure similar to that described in Example 3, 37.8
g. (0.1 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was
reacted with 0.18 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with 27 g. (0.23 mole)
of acetophenone to give 11.8 g. of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-.alpha.-methylbenzyl)phenyl]pr
opyl}piperidine as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.41 NO: C,83.00; H,9.85; N,3.34.
Found: C,83.34; H,9.97; N,3.23.
EXAMPLE 7
A solution of 0.15 mole of n-butyl lithium in 90 ml. of diethyl
ether was prepared by addition of 20.5 g. of n-butyl bromide in 30
ml. of ether to 2.58 g. (0.375 mole) of lithium. Sufficient volume
of the solution to provide 0.093 mole was added to a solution of
19.4 g. (0.051 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine (described
above in Example 3) in 100 ml. of ether. The mixture was stirred
for thirty minutes while maintaining the temperature below
10.degree. C., refluxed for thirty minutes, cooled once again below
10.degree. C., treated over a ten minute period with a solution of
13.3 g. (0.10 mole) of 4-methoxybenzonitrile in 80 ml. of ether,
stirred for an additional hour and a half at below 10.degree. C.,
then stirred overnight at ambient temperature and treated with 110
ml. of a solution prepared by dissolving 9 ml. of concentrated
sulfuric acid in 45 ml. of water and 108 ml. of dioxane. The
solution was refluxed for two hours, cooled, basified with 100 ml.
of 10% sodium hydroxide, the layers separated, and the aqueous
layer extracted with ether. The ether extracts were washed with
brine, dried and taken to dryness to give 32.6 g. of material which
was dissolved in hexane and extracted with a solution of 8 ml. of
concentrated sulfuric acid, 136 ml. of water and 144 ml. of
methanol. The extracts were rendered basic with 10% sodium
hydroxide, the mixture extracted once again with hexane, and the
hexane extracts washed with brine, dried and taken to dryness to
give 28.1 g. of material which was chromatographed on 400 g. of
alumina and eluted with 50% benzene/50% hexane. The first 1750 ml.
of eluate was taken to dryness, the residue heated in vacuo at 0.1
mm/220.degree. C. (bath temperature) to drive off some
4-methoxybenzonitrile, and the residue once again chromatographed
on alumina (250 g.) using 15% ether/85% hexane. The first 400 ml.
of eluate was discarded and the next 1200 ml., on evaporation to
dryness, afforded 7.1 g. of
2-cyclohexylmethyl-1-{2-[3-(4-methoxybenzoyl)phenyl]propyl}piperidine
as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.39 NO.sub.2 : C,80.33; H,9.07;
N,3.23. Found: C,80.50; H,9.17; N,3.14.
EXAMPLES 7A-7L
Following a procedure similar to that described in Examples 3, 4
and 5, the following compounds of formula I are similarly
prepared:
EXAMPLE 7A
2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]pyrrolidine,
(viscous amber liquid) prepared by reaction of 21.3 g. (0.1 mole)
of .alpha.-(3-bromophenyl)propionaldehyde with 31.4 g. (0.2 mole)
of 2-cyclohexylmethylpyrrolidine in benzene; conversion of the
resulting 33.7 g. of 1-[2-(3-bromophenyl)-1-propenyl]pyrrolidine to
the iminium chloride with ethereal hydrogen chloride; reduction of
the iminium chloride (34.0 g. ) with 6.4 g. (0.17 mole) of sodium
borohydride in dimethylformamide; reaction of 9.8 g. (0.027 mole)
of the resulting (18.8 g.)
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]pyrrolidine (b.p.
135.degree.-136.degree. C./0.02 mm.) with 0.05 mole of butyl
lithium followed by 6.2 g. (0.06 mole) of benzonitrile in diethyl
ether and decomposition of the product with a solution of 4 ml. of
concentrated sulfuric acid in 20 ml. of water and 50 ml. of dioxane
to give 5.1 g. of product.
Anal. Calcd. for C.sub.27 H.sub.35 NO: C,83.24; H,9.06; N,3.60.
Found: C,82.77; H,9.05; N,3.64.
EXAMPLE 7B
2-Cyclohexylmethyl-1-{2-[3-(4-fluorobenzoyl)phenyl]propyl}piperidine
(yellow oil) prepared by reaction of 18.9 g. (0.05 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.1
mole of butyl lithium in diethyl ether followed by 12.8 g. (0.11
mole) of 4-fluorobenzonitrile and decomposition of the product with
a solution of 3.8 ml. of concentrated sulfuric acid in 19 ml. of
water and 45 ml. of dioxane to give 6.5 g of product.
Anal. Calcd. for C.sub.28 H.sub.36 FNO: C,79.77; H,8.61; N,3.32.
Found: C,79.60; H,8.76; N,3.51.
EXAMPLE 7C
2-Cyclohexylmethyl-1-{2-[3-(4-methylbenzoyl)phenyl]propyl}piperidine
(9.7 g. as a yellow oil) prepared by reaction of 18.9 g. (0.05
mole) of 2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine
with 0.1 mole of butyl lithium in diethyl ether followed by 12.4 g.
(0.11 mole) of 4-methylbenzonitrile and decomposition of the
product with a solution of 3.8 ml. of concentrated sulfuric acid in
19 ml. of water and 45 ml. of dioxane to give 9.7 g. of
product.
Anal. Calcd. for C.sub.29 H.sub.39 NO: C,83.40; H,9.41; N,3.35.
Found: C,83.34; H,9.61; N,3.30.
EXAMPLE 7D
2-(3-Cyclohexylpropyl)-1-[2-(3-benzoylphenyl)propyl]piperidine
(yellow oil) prepared by reaction of 12.2 g. (0.03 mole) of
2-(3-cyclohexylpropyl)-1-[2-(3-bromophenyl)propyl]piperidine with
0.06 mole of butyl lithium in diethyl ether followed by 7.2 g.
(0.07 mole) of benzonitrile and decomposition of the product with a
solution of 8.3 ml. of concentrated sulfuric acid in 42 ml. of
water and 100 ml. of dioxane to give 6.2 g. of product.
Anal. Calcd. for C.sub.30 H.sub.41 NO: C,83.47;H,9.57; N,3.24.
Found: C,83.28; H,9.77; N,3.05.
EXAMPLE 7E
2-Cyclohexyl-1-[2-(3-benzoylphenyl)propyl]piperidine (light tan
oil) prepared by reaction of 12.7 g. (0.035 mole) of
2-cyclohexyl-1-[2-(3-bromophenyl)propyl]piperidine with 0.07 mole
of butyl lithium in diethyl ether followed by 8.9 g. (0.077 mole)
of benzonitrile and decomposition of the product with a solution of
9 ml. of concentrated sulfuric acid in 45 ml. of water and 100 ml.
of dioxane to give 6.1 g. of product.
Anal. Calcd. for C.sub.27 H.sub.35 NO: C,83.24; H,9.06; N,3.60.
Found: C,83.16; H,9.16; N,3.44.
EXAMPLE 7F
2-(2-Cyclohexylethyl)-1-[2-(3-benzoylphenyl)propyl]piperidine (pale
tan liquid) prepared by reaction of 13.7 g. (0.035 mole) of
2-(2-cyclohexylethyl)-1-[2-(3-bromophenyl)propyl]piperidine with
0.07 mole of butyl lithium in diethyl ether followed by 8.9 g.
(0.077 mole) of benzonitrile and decomposition of the product with
a solution of 9 ml. of concentrated sulfuric acid in 45 ml. of
water and 100 ml. of dioxane to give 8.9 g. of product.
Anal. Calcd. for C.sub.29 H.sub.39 NO: C,83.40; H,9.41; N,3.35.
Found: C,83.57; H,9.40; N,3.35.
EXAMPLE 7G
8-[2-(3-Benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane (pale
yellow oil) prepared by reaction of 10.6 g. (0.05 mole) of
.alpha.-(3-bromophenyl)propionaldehyde with 14.3 g. (0.1 mole) of
1,4-dioxa-8-azaspiro[4,5]decane in benzene; conversion of the
resulting 15.7 g. of
8-[2-(3-bromophenyl)-1-propenyl]-1,4-dioxa-8-azaspiro[4,5]decane to
the iminium chloride with ethereal hydrogen chloride; reduction of
the iminium chloride with 3.8 g. (0.08 mole) of sodium borohydride
in dimethylformamide; reaction of the resulting 17.5 g. (0.05 mole)
of 8-[2-(3-bromophenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane with
0.1 mole of butyl lithium followed by 15.5 g. (0.15 mole) of
benzonitrile in diethyl ether and decomposition of the product with
a solution of 6 ml. of concentrated sulfuric acid in 30 ml. of
water and 72 ml. of dioxane to give 5.1 g. of product.
Anal. Calcd. for C.sub.23 H.sub.27 NO.sub.3 : C,75.58; H,7.45;
N,3.83. Found: C,75.60; H,7.69; N,3.87.
Reaction of the free base with a molar equivalent of fumaric acid
gave 8-[2-(3-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane
fumarate, m.p. 152.degree.-160.degree. C. (from water).
EXAMPLE 7H
4-[2-(3-Benzoylphenyl)propyl]morpholine (pale yellow oil) prepared
by reaction of 21.3 g. (0.1 mole) of
.alpha.-(3-bromophenyl)propionaldehyde with 17.4 g. (0.2 mole) of
morpholine in benzene; conversion of the resulting 27.3 g. of
4-[2-(3-bromophenyl)-1-propenyl]morpholine to the iminium chloride
with ethereal hydrogen chloride; reduction of the iminium chloride
with 7.6 g. (0.2 mole) of sodium borohydride in dimethylformamide;
reaction of the resulting 19 g. of
4-[2-(3-bromophenyl)propyl]morpholine (b.p. 99.degree.-120.degree.
C./0.09 mm., n.sub.D.sup.24 =1.5477) with 0.1 mole of butyl lithium
followed by 15.5 g. (0.15 mole) of benzonitrile in diethyl ether
and decomposition of the product with 150 ml. of a solution made by
dissolving 6 ml. of concentrated sulfuric acid in 30 ml. of water
and 72 ml. of dioxane to give 7.5 g. of product.
Anal. Calcd. for C.sub.20 H.sub.23 NO.sub.2 : C,77.64; H,7.49;
N,4.53. Found: C,77.62, H,7.37; N,4.71.
A small amount of the free base was converted to the hydrochloride
salt to give 4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride
monohydrate, m.p. 151.degree.14 155.degree. C.
Anal. Calcd. for C.sub.20 H.sub.23 NO.sub.2.HCl.H.sub.2 O: C,66.02;
H,7.20; Cl,9.74. Found: C,66.37; H,7.24; Cl,9.59.
The racemic base was resolved into its individual epimers as
follows:
In two separate runs, solutions of 3.09 g. (0.01 mole) of the
racemic free base in 25 ml. of ethanol were treated, respectively,
with a solution of 3.76 g. (0.01 mole) of (-)-dibenzoyltartaric
acid monohydrate ([.alpha.].sub.D.sup.25 =-109.4.degree./methanol,
m.p. 93.degree.-95.degree. C.) and 3.76 g. (0.01 mole) of
(+)-dibenzoyltartaric acid monohydrate ([.alpha.].sub.D.sup.25
=+107.degree./methanol, m.p. 89.degree.-92.degree. C.). The
crystals which separated from the two solutions were collected,
washed with cold ethanol, then with diethyl ether and
recrystallized from ethanol to give, respectively, 3.7 g.
([.alpha.].sub.D.sup.25 =-70.0.degree./methanol, m.p.
141.degree.-141.5.degree. C.) and 2.83 g. ([.alpha.].sub.D.sup.25
=+70.7.degree./methanol, m.p. 144.degree.14 144.5.degree. C.) of
the respective l-base.l-acid and d-base.d-acid dibenzoyltartrate
salts, respectively.
Regeneration of the free bases from the salts by partitioning the
latter between diethyl ether and aqueous potassium carbonate,
isolating the free bases from the ether extracts and converting the
bases to the respective hydrochloride salts gave, respectively,
(-)-4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride,
[.alpha.].sub.D.sup.25 =-9.5.degree./methanol, m.p.
170.degree.-171.degree. C. and
(+)-4-[2-(3-benzoylphenyl)propyl]morpholine hydrochloride,
[.alpha.].sub.D.sup.25 =+13.3.degree./methanol, m.p.
169.degree.-170.degree. C.
EXAMPLE 7J
2,6-Dimethyl-4-[2-(3-benzoylphenyl)propyl]morpholine
cyclohexanesulfamate prepared by reaction of 21.3 g. (0.1 mole) of
.alpha.-(3-bromophenyl)propionaldehyde with 23 g. (0.2 mole) of
2,6-dimethylmorpholine in benzene; conversion of the resulting 28.4
g. of 2,6-dimethyl-4-[2-(3-bromophenyl)-1-propenyl]morpholine to
the iminium chloride with ethereal hydrogen chloride; reduction of
the iminium chloride with 10 g. (0.26 mole) of sodium borohydride
in dimethylformamide; reaction of the resulting 15.5 g. of
2,6-dimethyl-4-[2-(3-bromophenyl)propyl]morpholine (b.p.
125.degree.-129.degree. C./0.01 mm., n.sub.D.sup.24 =1.5294) with
0.1 mole of butyl lithium followed by 11 g. (0.11 mole) of
benzonitrile in diethyl ether and decomposition of the product with
150 ml. of a solution prepared by dissolving 45 ml. of concentrated
sulfuric acid in 225 ml. of wate and 540 ml. of dioxane. The
product was converted to the cyclohexanesulfamate salt which was
recrystallized from acetone to give 7.7 g. of product, m.p.
156.degree.14 158.degree. C.
Anal. Calcd. for C.sub.22 H.sub.27 NO.sub.2.C.sub.6 H.sub.13
NO.sub.3 S: C,65.08; H, 7.80; S,6.20. Found: C,64.86; H,7.72;
S,6.22.
EXAMPLE 7K
2-Cyclohexylmethyl-1-[2-(3-benzoyl-2-methylphenyl)ethyl]piperidine
prepared by reaction of 2-bromo-6-bromomethyltoluene [described by
Lindsay et al., J. Am. Chem. Soc. 83, 943-949 (1961)] with
potassium cyanide in refluxing ethanol; reduction of the resulting
(3-bromo-2-methylphenyl)acetonitrile with diisobutylaluminum
hydride; reaction of the resulting
(3-bromo-2-methylphenyl)acetaldehyde with
2-cyclohexylmethylpiperidine in refluxing benzene under a
Dean-Stark trap; reduction with sodium borohydride of the iminium
hydrochloride of the resulting
2-cyclohexylmethyl-1-[2-(3-bromo-2-methylphenyl)-1-ethenyl]piperidine;
and reaction of the resulting
2-cyclohexylmethyl-1-[2-(3-bromo-2-methylphenyl)ethyl]piperidine
with n-butyl lithium in diethyl ether followed by reaction of the
resulting lithio derivative with benzonitrile.
EXAMPLE 7L
4-[2-(3-Benzoyl-2-methylphenyl)ethyl]morpholine prepared by
reaction of (3-bromo-2-methylphenyl)acetaldehyde with morpholine in
refluxing benzene under a Dean-Stark trap; reduction with sodium
borohydride of the iminium hydrochloride of the resulting
4-[2-(3-bromo-2-methylphenyl)-1-ethenyl]morpholine; and reaction of
the resulting 4-[2-(3-bromo-2-methylphenyl)ethyl]morpholine with
n-butyl lithium in diethyl ether followed by reaction of the
resulting lithio derivative with benzonitrile.
EXAMPLE 8
Following a procedure similar to that described in Example 7, 18.9
g. (0.05 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was
reacted with 0.095 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with 12.4 g. (0.106
mole) of 2-methylbenzonitrile to give 4.85 g. of
2-cyclohexylmethyl-1-{2-[3-(2-methylbenzoyl)phenyl]propyl}piperidine
as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.39 NO: C,83.40; H,9.41; N,3.35.
Found: C,83.14; H,9.54; N,3.67.
EXAMPLE 9
Following a procedure similar to that described in Example 7, 18.9
g. (0.05 mole) of
2cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was reacted
with 0.095 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with 12.4 g. (0.106
mole) of 3-methylbenzonitrile to give 10.7 g. of
2-cyclohexylmethyl-1-{2-[3-(3-methylbenzoyl)phenyl]propyl}piperidine
as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.39 NO: C,83.40; H,9.41; N,3.35.
Found: C,83.06; H,9.38; N,3.48.
EXAMPLE 10
A solution of 13.0 g. (0.032 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine
(described above in Example 1) in 167 ml. of glacial acetic acid
and 33 ml. of perchloric acid was placed in a Parr hydrogenator and
reduced over 3.5 g. of 10% palladium-on-charcoal at ambient
temperature under a hydrogen pressure of 54 p.s.i. When reduction
was complete, the catalyst was removed by filtration, the filtrate
was taken to dryness, and the residue rendered basic with 10%
sodium hydroxide and extracted four times with hexane. The combined
hexane extracts were dried, taken to dryness, and the residue
chromatographed on 220 g. of alumina, and eluted with 10% ether/89%
hexane/1% isopropylamine. The first 350 ml. of eluate when taken to
dryness afforded 10.6 g. of
2-cyclohexylmethyl-1-[2-(3-benzylphenyl)propyl]piperidine as a
yellow oil.
Anal. Calcd. for C.sub.28 H.sub.39 N: C,86.32; H,10.09; N,3.59.
Found: C,86.18; H,10.34; N,3.51.
EXAMPLE 11
Following a procedure similar to that described in Example 10, 11.1
g. (0.027 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-.alpha.-methylbenzyl)phenyl]pr
opyl}piperidine (described in Example 6) dissolved in 180 ml. of
glacial acetic acid and 20 ml. of 72% perchloric acid was reduced
with hydrogen over 0.8 g. of palladium-on-charcoal to give 10.3 g.
of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-methylbenzyl)phenyl]propy}piperidine
as a yellow oil.
Anal. Calcd. for C.sub.29 H.sub.41 N: C,86.29; H,10.24; N,3.47.
Found: C,86.04; H,10.21; N,3.70.
EXAMPLE 12
A solution of 26.8 g. (0.066 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine
(described above in Example 1) in 140 ml. of benzene was vigorously
stirred and cooled to 16.degree. C. and then treated dropwise over
a period of ten minutes with 58 ml. of a solution prepared by
dissolving 26.7 g. of chromium trioxide in 23 ml. of concentrated
sulfuric acid and diluting with water to 100 ml. The mixture was
stirred with cooling for about one hour and forty-five minutes, the
benzene layer removed, and the aqueous layer made basic by addition
of 120 ml. of 10% sodium hydroxide and extracted with benzene. The
organic extracts, on washing once with dilute alkali, once with
brine, and evaporation to dryness, afforded 21.8 g. of an oil which
was chromatographed over 300 g. of alumina using 3% isopropylamine
in hexane as eluent. The first 600 ml. of eluate was collected and
taken to dryness to give 16.2 g. of
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine as a
pale yellow viscous oil.
Anal. Calcd. for C.sub.28 H.sub.37 NO: C,83.33; H,9.23; N,3.47.
Found: C,83.30; H,9.33; N,3.45.
EXAMPLE 13
Following a procedure similar to that described in Example 12, 15.2
g. (0.39 mole) of
2,6-dimethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine
(described above in Example 2) was oxidized with 34 ml. of a
solution prepared by dissolving 13.4 g. of chromium trioxide in
11.5 ml. of concentrated sulfuric acid and dilution with water to
50 ml. The product, in the form of the free base, was purified by
chromatographing on alumina using 10% ether/3% isopropylamine/87%
hexane as eluent. There was thus obtained 4.8 g. of
2,6-dimethyl-1-[2-(3-benzoylphenyl)propyl]piperidine as a colorless
viscous oil.
Anal. Calcd. for C.sub.23 H.sub.29 NO: C,82.34; H,8.71; N,4.18.
Found: C,82.23; H,8.82; N,4.15.
EXAMPLES 13A-13G
Proceeding in a manner similar to that described in Examples 1 and
12, the following compounds of formula I are obtained:
EXAMPLE 13A
2-Methyl-1-[2-(3-benzoylphenyl)propyl]hexamethyleneimine prepared
by reaction of .alpha.-(3-benzoylphenyl)propionylchloride with
2-methylhexamethyleneimine [Mueller et al., Monatsh. 61, 212-218
(1932)]; reduction with lithium aluminum hydride of the resulting
2-methyl-1-[.alpha.-(3-benzoylphenyl)propionyl]hexamethyleneimine;
and chromic acid oxidation of the resulting
2-methyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}hexamethyleneimine.
EXAMPLE 13B
4-Cyclohexyl-1-[2-(3-benzoylphenyl)propyl]piperidine prepared by
reaction of .alpha.-(3-benzoylphenyl)propionyl chloride with
4-cyclohexylpiperidine; reduction with lithium aluminum hydride of
the resulting
4-cyclohexyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperidine; and
chromic acid oxidation of the resulting
4-cyclohexyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine.
EXAMPLE 13C
3-Butyl-4-[2-(3-benzoylphenyl)propyl]morpholine prepared by
reaction of .alpha.-(3-benzoylphenyl)propionyl chloride with
3-butylmorpholine; reduction with lithium aluminum hydride of the
resulting 3-butyl-4-[.alpha.-(3-benzoylphenyl)propionyl]morpholine;
and chromic acid oxidation of the resulting
3-butyl-4-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}morpholine.
EXAMPLE 13D
3-Ethyl-4-[2-(3-benzoylphenyl)propyl]thiomorpholine prepared by
reaction of .alpha.-(3-benzoylphenyl)propionyl chloride with
3-ethylthiomorpholine; conversion of the resulting
3-ethyl-4-[.alpha.-(3-benzoylphenyl)propionyl]thiomorpholine to the
corresponding ethylene glycol ketal; reduction with lithium
aluminum hydride of the resulting ketal; and hydrolysis with dilute
mineral acid of the resulting
3-ethyl-4-[2-(3-benzoylphenyl)propyl]thiomorpholine ethylene glycol
ketal.
EXAMPLE 13E
4-Methyl-1-[2-(3-benzoylphenyl)propyl]piperazine prepared by
reaction of .alpha.-(3-benzoylphenyl)propionyl chloride with
1-methylpiperazine; reduction with lithium aluminum hydride of the
resulting
4-methyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine; and
chromic acid oxidation of the resulting
4-methyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperazine.
EXAMPLE 13F
3-Benzyl-1-[2-(3-benzoylphenyl)propyl]piperidine prepared by
reaction of .alpha.-(3-benzoylphenyl)propionyl chloride with
3-benzylpiperidine; reduction with lithium aluminum hydride of the
resulting
3-benzyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperidine; and
chromic acid oxidation of the resulting
3-benzyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]propyl}piperidine.
EXAMPLE 13G
N-[5-(N',N'-Dimethylamino)-2-pentyl]-N-[2-(3-benzoylphenyl)propyl]amine
prepared by reaction of .alpha.-(3-benzoylphenyl)propionyl chloride
with 5-(N',N'-dimethylamino)-2-pentylamine; reduction with lithium
aluminum hydride of the resulting
N-[5-(N',N'-dimethylamino-2-pentyl]-N-[.alpha.-(3-benzoylphenyl)propionyl]
amine; and chromic acid oxidation of the resulting
N-[5-(N',N'-dimethylamino-2-pentyl]-N-{2-[3-(.alpha.-hydroxybenzyl)phenyl]
-propyl}amine.
EXAMPLE 14
Following a procedure similar to that described in Example 7, 5.0
g. (13.2 mole) of
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine was
reacted with 0.026 mole of n-butyl lithium in diethyl ether and the
resulting lithio derivative reacted directly with benzonitrile to
give 4.0 g. of
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine
identical with the material described in Example 12.
A diastereoisomer of the same compound was prepared by the
following procedure. The
2-cyclohexylmethyl-1-[2-(3-bromophenyl)propyl]piperidine described
above in Example 3 (77.3 g.) was converted to the hydrochloride
salt by dissolving the base in 100 ml. of acetone and treating the
solution with 70 ml. of ethereal hydrogen chloride. The solvent was
evaporated in vacuo and the residue treated with another 100 ml. of
acetone and again evaporated to dryness. The residue was
recrystallized from 125 ml. of acetone and 150 ml. of ether, and
the solid which separated after standing for about twenty-four
hours at about 0.degree. C. was collected, washed with acetone and
dried to give 30.7 g. of the corresponding hydrochloride salt, m.p.
193.degree.-196.degree. C. Further recrystallization from 350 ml.
of acetonitrile afforded 23.9 g. of the purified diastereoisomer,
having m.p. 197.degree.-201.degree. C. An 18.4 g. portion of the
latter was reconverted to the free base by cleavage with dilute
alkali, extraction of the base into hexane and evaporation of the
hexane extracts to dryness.
The resulting free base (15.1 g., 0.04 mole) was converted to the
lithio derivative by reaction with 0.08 mole of n-butyl lithium in
diethyl ether (concentration 1.04 mmole/ml.), and the resulting
lithium derivative was reacted directly with 8.75 g. (0.085 mole)
of benzonitrile in 35 ml. of diethyl ether using the procedure
described above in Example 7. The product was isolated by
distilling the crude product in vacuo and chromatographing the
portion of sample which would not distill at an oil bath
temperature of 240.degree. C. at 0.10 mm. The product thus obtained
was converted to the hydrochloride salt which was recrystallized
from acetone/diethyl ether to give 4.38 g. of
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine
hydrochloride, m.p. 155.degree.-157.degree. C., one of the possible
diastereoisomers of the compound described above.
Anal. Calcd. for C.sub.28 H.sub.37 NO.HCl: C,76.42; H,8.70;
Cl,8.06. Found: C,76.22; H,8.67; Cl,8.16.
Following a procedure similar to that described in Example 14, the
following compound of formula I was similarly prepared:
EXAMPLE 14A
1-[2-(3-Benzoylphenyl)propyl]piperidine hydrochloride (m.p.
151.degree.-153.degree. C. from acetone) prepared by reaction of
16.3 g. (0.057 mole) of 1-[2-(3-bromophenyl)propyl]piperidine with
0.12 mole of butyl lithium in diethyl ether followed by 12.6 g.
(0.12 mole) of benzonitrile and decomposition of the product with a
solution of 45 ml. of concentrated sulfuric acid in 225 ml. of
water and 540 ml. of dioxane to give 6.5 g. of product.
Anal. Calcd. for C.sub.21 H.sub.25 NO.HCl: C,73.34; H,7.62;
Cl,10.31. Found: C,72.70; H,7.92; Cl,10.32.
EXAMPLE 15
A mixture of 37.5 g. (0.093 mole) of
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine
(described in Examples 12 and 14 above) and 10.0 g. (0.14 mole) of
hydroxylamine in 125 ml. of 95% ethanol and 25 ml of water was
treated with stirring with 19.4 g. of powdered sodium hydroxide and
the mixture refluxed for a half hour. The mixture was then cooled,
diluted with hexane, the aqueous layer separated, and the organic
layer, after drying, was evaporated to dryness to give 41.6 g. of a
yellow oil which was chromatographed on alumina in 30:70 diethyl
ether/hexane to give 37.3 g. of
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)propyl]piperidine oxime as
an oil.
Anal. Calcd. for C.sub.28 H.sub.38 N.sub.2 O: C,80.33; H,9.15;
N,6.69. Found: C,80.03; H,9.42; N,6.44.
EXAMPLES 15A-15C
Following a procedure similar to that described in Example 15, the
following compounds of formula I were similarly prepared:
EXAMPLE 15A
4-[2-(3-Benzoylphenyl)ethyl]morpholine oxime (m.p.
117.degree.-134.degree. C., from benzene/hexane) prepared by
reacting 18.15 g. (0.05 mole) of
4-[2-(3-benzoylphenyl)ethyl]morpholine hydrochloride with 5.6 g.
(0.08 mole) of hydroxylamine hydrochloride in the presence of 12.5
g. (0.31 mole) of sodium hydroxide in 70 ml. of ethanol and 18.5
ml. of water to give 14.06 g. of product.
Anal. Calcd. for C.sub.19 H.sub.22 N.sub.2 O.sub.2 : C,73.52;
H,7.14; N,9.03. Found: C,73.79; H,7.26; N,8.72.
EXAMPLE 15B
4-(3-Benzoylphenyl)methylmorpholine oxime (m.p.
145.degree.-167.degree. C.) prepared by reaction of 28.62 g. (0.09
mole) of 4-(3-benzoylphenyl)methylmorpholine hydrochloride with
9.63 g. (0.14 mole) of hydroxylamine hydrochloride in the presence
of 21.68 g. (0.54 mole) of sodium hydroxide in 35 ml. of ethanol
and 27 ml. of water to give 13.9 g. of product.
EXAMPLE 15C
4-[2-(3-Benzoylphenyl)propyl]morpholine oxime (m.p.
117.degree.-130.degree. C., from isopropanol) prepared by reaction
of 27 g. (0.078 mole) of 4-[2-(3-benzoylphenyl)propyl]morpholine
hydrochloride with 8.2 g. (0.117 mole) of hydroxylamine
hydrochloride in the presence of 18.8 g. (0.47 mole) of sodium
hydroxide in 115 ml. of ethanol and 27 ml. of water to give 3.2 g.
of product.
EXAMPLE 16
A solution of 17 g. (0.041 mole) of the
2-cyclohexylmethyl-1-[2-(3-benzoylphenyl)porpyl]piperidine oxime
described above in Example 15 in 110 ml. of ethanol was brought to
reflux and treated with 10 g. (0.043 mole) of sodium metal, added
in small pieces. Refluxing was continued until all sodium had
dissolved, and the solution was then cooled, diluted with 140 ml.
of water, evaporated to a volume of about 150 ml. in vacuo, and
then extracted with three portions of benzene. Evaporation of the
benzene extracts to dryness afforded 14.2 g. of an oil which was
converted to the acetate salt by dissolving in chloroform, adding
glacial acetic acid and evaporation to dryness. The acetate salt
was again dissolved in chloroform and chromatographed on alumina,
eluting with chloroform. The acetate hydrolyzed on the column, and
the free base obtained from the eluate was dissolved in ethanol,
and the solution acidified with ethereal hydrogen chloride and
evaporated to dryness to give 6.38 g. of 2-cyclohexylmethyl-1-{2-[3
-(.alpha.-aminobenzyl)phenyl]propyl}piperidine dihydrochloride,
m.p. 167.degree.-195.degree. C.
Anal. Calcd. for C.sub.28 H.sub.41 N.sub.2.2HCl: N,5.87; Cl,14.85.
Found: N,5.61; Cl,14.66.
EXAMPLES 16A-16C
Following a procedure similar to that described in Example 16, the
following compounds of formulas I and Ia were similarly
prepared:
EXAMPLE 16A
4-{2-[3-(.alpha.-Aminobenzyl)phenyl]ethyl}-morpholine
dihydrochloride, m.p. 260.degree.-263.degree. C. (15.42 g. from
methanol/diethyl ether) prepared by reducing 14.55 g. (0.047 mole)
of 4-[2-(3-benzoylphenyl)ethyl]morpholine oxime with 11.5 g. (0.50
mole) of sodium in 100 ml. of absolute ethanol.
Anal. Calcd. for C.sub.19 H.sub.24 N.sub.2 O.2HCl: C,61.79; H,7.10;
Cl,19.20. Found: C,61.88; H,6.90; Cl,19.16.
EXAMPLE 16B
4-{[3-(.alpha.-Aminobenzyl)phenyl]methyl}morpholine dihydrochloride
monohydrate, m.p. 270.degree.-274.degree. C. (8.3 g., from
methanol/ether) prepared by reduction of 8.12 g. (0.027 mole) of
4-[(3-benzoylphenyl)methyl]morpholine oxime with 6.45 g. (0.28
mole) of sodium in absolute ethanol.
Anal. Calcd. for C.sub.18 H.sub.22 N.sub.2 O.2HCl.H.sub.2 O:
C,60.84; H,6.81; Cl,19.96. Found: C,60.68; H,6.83; Cl,20.27.
EXAMPLE 16C
4-{2-[3-(.alpha.-Aminobenzyl)phenyl]propyl}morpholine
dihydrochloride m.p. 255.degree.-265.degree. C. (9.5 g., from
methanol/diethyl ether) prepared by reduction of 10.0 g. (0.03
mole) of 4-[2-(3-benzoylphenyl)propyl]morpholine oxime with 7.1 g.
(0.31 mole) of sodium in 65 ml. of absolute ethanol.
Anal. Calcd. for C.sub.20 H.sub.26 N.sub.2 O.2HCl: C,62.66; H,7.36;
Cl,18.50. Found: C,61.78; H,7.17; Cl,18.01.
EXAMPLE 17
A solution of 13.0 g. (0.031 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-.alpha.-methylbenzyl)phenyl]pr
opyl}piperidine (described in Example 6) in 130 ml. of methanol and
3 ml. of concentrated sulfuric acid was stirred and refluxed for
forty-five minutes, then cooled, diluted with 100 ml. of water,
basified with 5 ml. of 35% sodium hydroxide and extracted with
hexane. The combined hexane extracts, on washing with brine, drying
and evaporation to dryness gave 14.2 g. of an oil which was
chromatographed on 260 g. of alumina in 8:92 diethyl ether/hexane.
There was thus obtained 9.8 g. of
2-cyclohexylmethyl-1-{2-[3-(1-phenyl-1-vinyl)phenyl]propyl}-piperidine
as an oil.
Anal. Calcd. for C.sub.29 H.sub.39 N: C,86.72; H,9.79; N,3.49.
Found: C,86.79; H,9.76; N,3.28.
EXAMPLE 18
4-Methoxyphenylacetic acid (41.5 g., 0.25 mole) was converted to
the corresponding acid chloride with 47.7 g. (0.4 mole) of thionyl
chloride in benzene using the procedure described above in Example
1. The acid chloride thus produced (36.8 g., 0.2 mole) was reacted
with 24.1 g. (0.21 mole) of 2,6-dimethylpiperidine in ether in the
presence of 24.2 g. (0.24 mole) of triethylamine using the
procedure described above in Example 1. The resulting
2,6-dimethyl-1-[(4-methoxyphenyl)acetyl]piperidine (38.8 g., 0.15
mole) was reduced with lithium aluminum hydride and the product
isolated in the form of the hydrochloride salt to give 15.32 g. of
2,6-dimethyl-1-[2-(4-methoxyphenyl)ethyl]piperidine hydrochloride,
m.p. 195.degree.-200.degree. C.
The latter (1.0 g., 0.004 mole), in the form of the free base, was
added in small portions to a stirred mixture of 1.21 g. (0.009
mole) of aluminum chloride and 1.28 g. (0.009 mole) of benzoyl
chloride. The resulting viscous mixture was stirred for about
twelve hours at ambient temperature and then mixed with ice, 2 ml.
of concentrated hydrochloric acid and 2 ml. of water. The resulting
mixture was extracted with chloroform, and the chloroform extracts
washed with brine, dried and evaporated to dryness to give
2,6-dimethyl-1-[2-(3-benzoyl-4-methoxyphenyl)ethyl]piperidine as a
yellow oil.
EXAMPLE 19
A mixture of 45 g. (0.13 mole) of
2,6-dimethyl-1-[2-(3-benzoyl-4-methoxyphenyl)ethyl]piperidine
(described above in Example 18) and 34.9 g. (0.26 mole) of aluminum
chloride in tetrachloroethane was heated and stirred at 50.degree.
C. for about twelve hours and then poured into a solution of 30 ml.
of concentrated hydrochloric acid and 30 ml. of ice water. The
mixture was basified with sodium carbonate, extracted four times
with chloroform, and the chloroform extracts washed with saturated
brine, dried and evaporated to dryness to give crude product which
was once again heated for twelve hours at 50.degree. C. with 30 g.
of aluminum chloride and 30 ml. of tetrachloroethane. On working up
as before, there was obtained 8 g. of crude material which was
dissolved in chloroform. The organic solution was washed five times
with 10% sodium carbonate, once with brine, then dried and taken to
dryness. The residue was dissolved in acetone, and the solution was
treated with ethereal hydrogen chloride to give solid material
which was recrystallized from isopropanol. There was thus obtained
5.8 g. of 2,6-dimethyl-1-[2-(
3-benzoyl-4-hydroxyphenyl)ethyl]piperidine hydrochloride, m.p.
217.degree.-219.degree. C.
Anal. Calcd. for C.sub.22 H.sub.27 NO.sub.2.HCl: C,70.67; H,7.55;
N,3.75. Found: C,70.87; H,7.58; N,3.73.
EXAMPLE 20
A solution of 13.2 g. (0.03 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-4-chlorobenzyl)phenyl]propyl}p
iperidine (described above in Example 5), 16 ml. of concentrated
nitric acid and 32 ml. of 50% perchloric acid in 160 ml. of
1,2-dimethoxyethane was heated under reflux for one and a quarter
hours, then cooled, diluted with 50 ml. of water, basified with 150
ml. of 10% sodium hydroxide and extracted with hexane. The hexane
extracts were washed once with water, once with brine, dried and
evaporated to dryness to give 12 g. of crude product which was
chromatographed on 200 g. of alumina using 10:90 ether/hexane as
eluent. The first 75 ml. of eluate was discarded and the next 600
ml. was taken to dryness to yield 9.2 g. of
2-cyclohexylmethyl-1-{2-[3-(4-chlorobenzoyl)phenyl]propyl}piperidine.
Anal. Calcd. for C.sub.28 H.sub.36 ClNO: C,76.77; H,8.28; Cl,8.09.
Found: C,76.85; H,8.35; Cl,8.27.
EXAMPLES 20A-20D
Following a procedure similar to that described in Example 20, the
following compounds of formula I were similarly prepared:
EXAMPLE 20A
2-Cyclohexylmethyl-1-[2-(3-benzoylphenyl)ethyl]piperidine (yellow
oil) prepared by oxidation of 14.0 g. (0.03 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxybenzyl)phenyl]ethyl}piperidine
(described above in Example 1A) in 227 ml. of a solution prepared
by dissolving 44.5 ml. of 72% perchloric acid, 20 ml. of water and
32 ml. of concentrated nitric acid in 320 ml. of
1,2-dimethoxyethane. There was thus obtained 8.74 g. of
product.
Anal. Calcd. for C.sub.27 H.sub.35 NO: C,83.24; H,9.06; N,3.60.
Found: C,83.46; H,9.26; N,3.75.
EXAMPLE 20B
2-Cyclohexylmethyl-1-{2-[3-(3-chlorobenzoyl)phenyl]propyl}piperidine
(yellow oil) prepared by oxidation of 17.0 g. (0.039 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-3-chlorobenzyl)phenyl]propyl}p
iperidine (described above in Example 3A) in 244 ml. of a solution
prepared by dissolving 48 ml. of 50% perchloric acid and 24 ml. of
concentrated nitric acid in 240 ml. of 1,2-dimethoxyethane. There
was thus obtained 9.65 g. of product.
Anal. Calcd. for C.sub.28 H.sub.36 ClNO: C,76.77; H,8.28; N,3.20.
Found: C,76.86; H,8.36; N,3.13.
EXAMPLE 20C
2-Cyclohexylmethyl-1-{2-[3-(3,4-dichlorobenzoyl)phenyl]propyl}piperidine
(yellow oil) prepafred by oxidation of 11.9 g. (0.25 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-3,4-dichlorobenzyl)phenyl]prop
yl}piperidine (described above in Example 3C) in 156 ml. of a
solution prepared by dissolving 24 ml. of 50% perchloric acid and
12 ml. of concentrated nitric acid in 120 ml. of
1,2-dimethoxyethane. There was thus obtained 5.2 g. of product.
Anal. Calcd. for C.sub.28 H.sub.35 Cl.sub.2 NO: C,71.18; H,7.47;
N,2.96. Found: C,71.47; H,7.82; N,2.96.
EXAMPLE 20D
2-Cyclohexylmethyl-1-{2-[3-(2-chlorobenzoyl)phenyl]propyl}piperidine
(yellow oil) prepared by oxidation of 15.7 g. (0.036 mole) of
2-cyclohexylmethyl-1-{2-[3-(.alpha.-hydroxy-2-chlorobenzyl)phenyl]propyl}p
iperidine (described above in Example 3D) in 225 ml. of a solution
prepared by dissolving 48 ml. of 50% perchloric acid and 24 ml. of
concentrated nitric acid in 240 ml. of 1,2-dimethoxyethane. There
was thus obtained 6.4 g. of product.
Anal. Calcd. for C.sub.28 N.sub.36 ClNO: C,76.77; H,8.38; N,3.20.
Found: C,76.47; H,8.58; N,3.09.
EXAMPLE 21
A solution of 11.0 g. (0.126 mole) of morpholine in 24 ml. of
dimethylformamide was stirred with external cooling in a water bath
and treated over a ten minute period with a solution of 17.35 g.
(0.06 mole) of 1-(3-benzoylphenyl)-1-bromoethane in 24 ml. of
dimethylformamide. When addition was complete the mixture was
stirred for an additional hour at ambient temperature. The mixture
was then filtered, the filter washed with ether, the filtrate
poured into 125 ml. of water and the mixture extracted twice with
ether. Isolation of the product in the form of the free base from
the ether extracts in the conventional manner afforded 14.8 g. of
oily product which was chromatographed on alumina using a 1:1
ether:hexane solution as element to give 12 g. of
4-[1-(3-benzoylphenyl)ethyl]morpholine as a pale yellow oil.
Anal. Calcd. for C.sub.19 H.sub.21 NO.sub.2 : C,77.26; H,7.17;
N,4.74. Found: C,76.95; H,7.11; N,4.61.
EXAMPLE 22
4-{2-[3-(.alpha.-Aminobenzyl)phenyl]ethyl}-morpholine (15.6 g.,
0.05 mole, described in Example 16A) was mixed with 13.8 g. (0.30
mole) of 97% formic acid and 9.4 g. (0.11 mole) of 35% formaldehyde
solution. The mixture was heated to 95.degree. C. to effect
complete solution of the gummy base, heating was continued for ten
hours, and the solution was cooled and poured into a dilute sodium
hydroxide/ice mixture. Isolation of the organic material in the
usual manner by extraction with ether afforded 15.6 g. of an oil
which was chromatographed on 400 g. of alumina using 1.5:98.5
isopropylamine:hexane as eluent. The first ten fractions, 75 ml.
each, were collected and set aside, and the next ten fractions,
75-100 ml. each, were combined and taken to dryness to give 10.6 g.
of 4-{2-[3-(.alpha.-dimethylaminobenzyl)phenyl]ethyl}morpholine as
an oil which crystallized on standing, m.p. 60.degree.-63.degree.
C.
Anal. Calcd. for C.sub.21 H.sub.28 N.sub.2 O: C,77.74; H,8.70;
N,8.63. Found: C,77.20; H,8.60; N,8.48.
EXAMPLE 23
Reaction of the
2-cyclohexylmethyl-1-{2-[3-(4-methoxybenzoyl)phenyl]propyl}piperidine
described above in Example 7 with hydrobromic acid in glacial
acetic acid, and isolation of the product from a neutral medium
affords
2-cyclohexylmethyl-1-{2-[3-(4-hydroxybenzoyl)phenyl]propyl}piperidine.
EXAMPLES 24A-24M
EXAMPLE 24A
A mixture of 23 g. (1.0 mole) of sodium cut into small pieces in
1.2 liters of isopropanol was stirred and refluxed until all solid
had dissolved. The mixture was then cooled to room temperature and
treated with a solution of 159.2 g. (0.8 mole) of
4-bromoacetophenone and 122.5 g. (1.0 mole) of ethyl chloroacetate
in 200 ml. of isopropanol. The mixture was stirred in an ice bath
for seventeen hours during which time the temperature of the
reaction mixture gradually rose to room temperature as the ice
melted. Removal of the solvent in vacuo afforded a dark brown
residual oil which was dissolved in 500 ml. of benzene and washed
twice with cold water and then with saturated brine. The organic
solution, on filtration, drying and evaporation to dryness afforded
a dark brown oil which was distilled in vacuo to give 227.2 g. of
ethyl 2-methyl-2-(4-bromophenyl)glycidate, b.p.
96.degree.-113.degree. C./0.08 mm.
A mixture of the latter (226 g., 0.8 mole) in a solution of 36.8 g.
(0.92 mole) of sodium hydroxide in 200 ml. of water and 200 ml. of
ethanol was heated under reflux for eighteen hours and the solvent
removed in vacuo. The residue was dissolved in 700 ml. of water and
extracted two times with 100 ml. portions of benzene. The aqueous
solution was filtered, acidified with 90 ml. of concentrated
hydrochloric acid and the mixture steam distilled. The distillate
was extracted with methylene dichloride, and the extracts were
filtered, dried, and taken to dryness in vacuo to give 126 g. of a
pale yellow oil which was distilled in vauo to give 125 g. of
.alpha.-(4-bromophenyl)propionaldehyde, b.p. 61.degree.-65.degree.
C./0.08-0.13 mm.
A solution of 42.6 g. (0.2 mole) of the latter in 400 ml. of
absolute methanol was treated with 15.14 g. (0.40 mole) of sodium
borohydride, added in portions over a period of about twenty
minutes, while maintaining the temperature around 20.degree. C. The
mixture was stirred for about four hours, then treated with 40-50
ml. of acetone and evaporated to dryness in vacuo. The residue was
shaken with a mixture of 250 ml. of benzene and 350 ml. of 25%
aqueous potassium hydroxide, and the organic layer was washed with
water, then with brine, dried and evaporated to dryness to give
59.56 g. of an oil which was distilled in vacuo to give 38.1 g. of
2-(4-bromophenyl)propanol, b.p. 109.degree.-117.degree. C./0.04
mole.
The latter was dissolved in about a three molar excess of
dihydropyran, the mixture was treated with about seven drops of
concentrated hydrochloric acid, and the solution allowed to stand
at ambient temperature for about eighteen hours. The mixture was
then treated with solid sodium bicarbonate to decompose the acid
present, the excess solvent was removed in vacuo, and the residue
was distilled in vacuo to give 38.0 g. of 2-(4-bromophenyl)propanol
tetrahydropyranyl ether, b.p. 118.degree.-124.degree. C./0.3 mm.,
n.sub.D.sup.23 =1.5305.
A solution of the latter (17.9 g., 0.06 mole) in 150 ml. of
anhydrous diethyl ether was treated with 35.0 ml. of a 2.04 M
solution of n-butyl lithium in hexane, and the solution was stirred
at -10.degree. to -5.degree. C. for about forty-five minutes, then
at about 0.degree. to 25.degree. C. for about two hours. The
mixture was then cooled to -10.degree. C. and treated over a
fifteen minute period at -10.degree. to -5.degree. C. with a
solution of 8.2 g. (0.08 mole) of benzonitrile in 50 ml. of
anhydrous diethyl ether. The mixture was stirred in an ice bath for
five hours, then for about twelve hours at ambient temperature. The
mixture was once again cooled to about 5.degree. C. and treated
with 75 ml. of 6 N hydrochloric acid and 75 ml. of water, and the
two-phase system was stirred and heated under reflux for about
three and a half hours. The mixture was filtered, the organic phase
was separated from the aqueous phase, and the latter was extracted
with additional portions of diethyl ether. The combined ether
extracts were washed with water, then with brine, filtered, dried
and evaporated to dryness to give 13.95 g. of an oil which was
distilled in vacuo to give 7.70 g. of 2-(4-benzoylphenyl)propanol,
b.p. 165.5.degree. C./0.04 mm; n.sub.D.sup.24 =1.5930.
A solution of 7.20 g. (0.03 mole) of the latter in 20 ml. of dry
pyridine was treated with a solution of 6.66 g. (0.30 mole) of
p-toluenesulfonyl chloride in 25 ml. of pyridine, and the solution
was allowed to stand at ambient temperature for about twenty hours.
The mixture was then evaporated in vacuo to a volume of about 20
ml., then diluted with 200 ml. of water and extracted with diethyl
ether. The ether extracts were washed first with water, then with
dilute hydrochloric acid, then with dilute potassium hydroxide,
once again with water, filtered, dried and evaporated to dryness to
give a viscous oil weighing 11.2 g. The latter was crystallized
from hexane to give 9.09 g. of 2-(4-benzoylphenyl)propyl
p-toluenesulfonate, m.p. 79.degree.-81.degree. C.
A solution of 11.8 g. (0.03 mole) of the latter and 10.4 g. (0.12
mole) of morpholine in 250 ml. of acetonitrile was heated under
reflux for fifty-three hours and then taken to dryness in vacuo,
the last traces of morpholine being removed by heating under high
vacuum for several hours. The residue was partitioned between
diethyl ether and water, the aqueous layer was washed several times
with additional portions of ether, and the combined ether extracts
were dried and taken to dryness. The residue was dissolved in
diethyl ether, the solution was treated with ethereal hydrogen
chloride, and the solid which separated was collected and
recrystallized from acetone to give 9.5 g. of
4-[2-(4-benzoylphenyl)propyl]morpholine hydrochloride, m.p.
207.degree.-208.degree. C.
Following a procedure similar to that described in Example 24A, the
following compounds of formula I were prepared:
EXAMPLE 24B
Reaction of 11.8 g. (0.03 mole) of 2-(4-benzoylphenyl)propyl
p-toluenesulfonate with 12.3 g. (0.09 mole) of
1,4-dioxa-8-azaspiro[4,5]decane in 250 ml. of acetonitrile and
isolation of the product in the form of the hydrochloride salt gave
12.4 g. of
8-[2-(4-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane
hydrochloride, m.p. 211.degree.-212.degree. C. (from diethyl
ether).
EXAMPLE 24C
Reaction of 2-(4-benzoylphenyl)propyl p-toluenesulfonate with
1-benzylpiperazine in acetonitrile and isolation of the product in
the form of the free base affords
1-[2-(4-benzoylphenyl)propyl]-4-benzylpiperazine. Conversion of the
latter to the ethylene glycol ketal, catalytic reduction of the
latter over palladium-on-charcoal at a hydrogen pressure of 50
p.s.i. in order to effect catalytic debenzylation thereof using the
manipulative procedure described in Example 10 above, cleavage of
the ketal with aqueous hydrochloric acid, and isolation of the
product in the form of the dihydrochloride salt affords
1-[2-(4-benzoylphenyl)propyl]piperazine dihydrochloride, m.p.
243.degree.-245.degree. C. (from ethanol).
EXAMPLE 24D
Reaction of 11.7 g. (0.03 mole) of 2-(4-benzoylphenyl)propyl
p-toluenesulfonate with 9.30 g. (0.09 mole) of thiomorpholine in 45
ml. of acetonitrile and isolation of the product in the form of the
hydrochloride salt gave 6.7 g. of
4-[2-(4-benzoylphenyl)propyl]thiomorpholine hydrochloride, m.p.
197.degree.-198.degree. C. (from acetone).
EXAMPLE 24E
A solution of 76.8 g. (0.5 mole) of 4,4-dihydroxypiperidine
hydrochloride, 50.0 g. (0.54 mole) of 1,2-ethanedithiol and 0.3 g.
of p-toluenesulfonic acid in 600 ml. of toluene was refluxed with
stirring under a Dean-Stark water trap until no further water was
given off. The solid which separated from the reaction mixture was
collected, partitioned between aqueous saturated potassium
carbonate solution and chloroform, the chloroform separated, and
the aqueous layer was extracted with additional portions of
chloroform. The combined chloroform extracts were dried and taken
to dryness to give 65.63 g. of an oil which was distilled in vacuo
to give 14.94 g. of 1,4-dithia-8-azaspiro[4,5]decane, b.p.
128.degree.-154.degree. C./18-20 mm., n.sub.D.sup.23 =1.5856.
Reaction of 12.74 g. (0.073 mole) of the latter with 9.56 g. (0.024
mole) of 2-(4-benzoylphenyl)propyl p-toluenesulfonate in 100 ml. of
acetonitrile and isolation of the product in the form of the
hydrochloride salt gave 8.65 g. of
8-[2-(4-benzoylphenyl)propyl-1,4-dithia-8-azaspiro[4,5]decane
hydrochloride, m.p. 261.degree.-263.degree. C. (from
isopropanol).
EXAMPLE 24F
Following a procedure similar to that described in Example 24E, a
solution of 51.0 g. (0.33 mole) of 4,4-dihydroxypiperidine
hydrochloride 26.0 g. (0.33 mole) of 2-mercaptoethanol and 0.5 g.
of p-toluenesulfonic acid in 500 ml. of toluene was refluxed under
a Dean-Stark trap until no further water was given off, and the
product was purified by distillation in vacuo to give 21.9 g. of
1-oxa-4-thia-8-azaspiro[4,5]decane, b.p. 116.5.degree.-123.degree.
C./14.5 mm., n.sub.D.sup.23 =1.5390.
Reaction of 17.38 g. (0.118 mole) of the latter with 15.43 g.
(0.039 mole) of 2-(4-benzoylphenyl)propyl p-toluenesulfonate in 75
ml. of acetonitrile and isolation of the product in the form of the
hydrochloride salt gave 13.72 g. of
8-[2-(4-benzoylphenyl)propyl]-1-oxa-4-thia-8-azaspiro[4,5]decane
hydrochloride, m.p. 229.degree.-231.degree. C. (from diethyl
ether/ethanol).
EXAMPLE 24G
Reaction of 199.0 g. (1.0 mole) of 3-bromoacetophenone with 175.5
g. (1.4 moles) of ethyl chloroacetate in the presence of 1.4 mole
of sodium ethoxide (prepared by dissolving 32.2 g. of sodium in
1550 ml. of absolute ethanol) and purification of the product by
distillation in vacuo gave 206.6 g. of ethyl
2-methyl-2-(3-bromophenyl)glycidate, b.p. 101.degree.-112/0.15 mm.,
n.sub.D.sup.27 =1.5330.
Saponification of the latter (206 g., 0.72 mole) with 0.76 mole of
sodium methoxide in ethanol followed by addition of 16 g. of water
and purification of the product by distillation in vacuo gave 72.9
g. of .alpha.-(3-bromophenyl)propionaldehyde, b.p.
69.degree.-78.degree. C./0.15-0.3 mm., n.sub.D.sup.30 =1.5544.
Reduction of 108.9 g. (0.51 mole) of the latter with 38.8 g. (1.02
moles) of sodium borohydride in 1 liter of absolute methanol and
purification of the product by distillation in vacuo gave 100.2 g.
of 2-(3-bromophenyl)propanol, b.p. 73.9.degree.-76.5.degree.
C./0.8-0.9 mm., n.sub.D.sup.24 =1.5638.
Reaction of 107.5 g. (0.5 mole) of the latter with 84.1 g. (1.0
mole) of dihydropyran in the presence of 0.3 g. of anhydrous
p-toluenesulfonic acid gave 152.2 g. of 2-(3-bromophenyl)propanol
tetrahydropyranyl ether as an oil.
Reaction of 229.5 g. (0.75 mole) of the latter with 0.975 mole of
n-butyl lithium, followed by reaction of the resulting lithium
derivative with 112.5 g. (1.09 moles) of benzonitrile in a total of
680 ml. of diethyl ether, hydrolysis of the resulting iminium
compound, cleavage of the pyranyl ether and purification of the
product by distillation in vacuo gave 102.1 g. of
2-(3-benzoylphenyl)propanol, b.p. 127.degree.-153.degree.
C./0.02-0.025 mm., n.sub.D.sup.24 =1.5964.
Reaction of 67.2 g. (0.28 mole) of the latter with 59.1 g. (0.31
mole) of p-toluenesulfonyl chloride in 300 ml. of pyridine and
purification of the product by recrystallization from cyclohexane
gave 81.6 g. of 2-(3-benzoylphenyl)propyl p-toluenesulfonate, m.p.
53.degree.-58.degree. C.
Reaction of the latter with a molar excess of 1-benzylpiperazine in
acetonitrile gives 1-[2-(3-benzoylphenyl)propyl]-4-benzylpiperazine
which, on catalytic debenzylation over palladium-on-charcoal under
a hydrogen pressure of about 50 p.s.i. of hydrogen, gives
1-[2-(3-benzoylphenyl)propyl]piperazine dihydrochloride, m.p.
236.degree.-239.degree. C. (from ethanol).
EXAMPLE 24H
To a stirred suspension of 11.0 g. (0.46 mole) of sodium hydride in
275 ml. of DMF was added a solution of 47.0 g. (0.18 mole) of ethyl
.alpha.-(3-bromophenyl)propionate in 250 ml. of dry DMF over a
thirty minute period. The mixture was stirred at ambient
temperature for about fifteen minutes and treated with 65 g. (0.46
mole) of methyl iodide added dropwise over a period of about forty
minutes. When addition was complete the mixture was stirred at
ambient temperature for about two hours and then diluted with two
liters of anhydrous diethyl ether. The mixture was filtered, the
filter washed with small portions of diethyl ether, and the
combined ether extracts, after acidification with concentrated
hydrochloric acid, were taken to dryness to give a dark oil which
was dissolved once again in diethyl ether and extracted with sodium
bicarbonate. The organic layer was separated, dried, taken to
dryness and the residual oil distilled in vacuo to give 66.9 g. of
ethyl .alpha.-(3-bromophenyl)-.alpha.,.alpha.-dimethylacetate, b.p.
53.degree.-55.degree. C./0.02 mm., n.sub.D.sup.23 =1.5234.
Saponification of the latter with aqueous potassium hydroxide and
absolute ethanol afforded the corresponding
.alpha.-(3-bromophenyl)-.alpha.,.alpha.-dimethylacetic acid, m.p.
71.degree.-73.degree. C.
The latter (94.1 g., 0.39 mole) was dissolved in 400 ml. of
anhydrous diethyl ether and reduced with 22.0 g. (0.58 mole) of
lithium aluminum hydride using the procedure described above in
Example 1A. The product was purified by distillation in vacuo to
give 73.75 g. of 2,2-dimethyl-2-(3-bromophenyl)ethanol, b.p.
57.degree.-58.degree. C./0.02 mm. as an oil which solidified. The
latter was recrystallized from hexane to give material having m.p.
46.degree.-48.degree. C.
Reaction of 48.5 g. (0.214 mole) of the latter with 35.6 g. (0.42
mole) of dihydropyran in the presence of 0.1 g. of
p-toluenesulfonic acid gave 67.2 g. of
2,2-dimethyl-2-(3-bromophenyl)ethanol tetrahydropyranol ether as an
oil.
Reaction of 67.2 g. (0.21 mole) of the latter with 0.26 mole of
n-butyl lithium and reaction of the lithium derivative with 29.9 g.
(0.29 mole) of benzonitriole, followed by hydrolysis of the
resulting imine, cleavage of the pyranyl ether and purification of
the product by distillation in vacuo, gave 41.8 g. of
2,2-dimethyl-2-(3-benzoylphenyl)ethanol, b.p.
151.degree.-160.degree. C./0.02-0.03 mm., n.sub.d.sup.25
=1.5904.
Reaction of 41.77 g. (0.16 mole) of the latter with 34.4 g. (0.18
mole) of p-toluenesulfonyl chloride in 125 ml. of pyridine gave
69.96 g. of 2,2-dimethyl-2-(3-benzoylphenyl)ethanol
p-toluenesulfonate. A small sample recrystallized from cyclohexane
gave material having m.p. 65.5.degree.-67.degree. C.
Reaction of 12.5 g. (0.03 mole) of the latter with 26.0 g. (0.30
mole) of morpholine in 50 ml. of N-methyl-2-pyrrolidinone and
isolation of the product in the form of the hydrochloride salt gave
14.3 g. of 4-[2,2-dimethyl-2-(3-benzoylphenyl)ethyl]morpholine
hydrochloride, m.p. 173.5-174.5.degree. C. (from acetone).
Example 24J
Reaction of 10.0 g. (0.024 mole) of
2,2-dimethyl-2-(3-benzoylphenyl)ethyl p-toluenesulfonate with 27.4
g. (0.19 mole) of 1,4-dioxa-8-azaspiro[4,5]decane in 40 ml. of
N-methyl-2-pyrrolidinone and isolation of the product in the form
of the hydrochloride salt gave 8.1 g. of
8-[2,2-dimethyl-2-(3-benzoylphenyl)ethyl]1,4-dioxa-8-azaspiro[4,5]decane
h ydrochloride, m.p. 201.degree.14 203.degree. C. (from
acetone).
Example 24K
Reaction of 12.1 g. (0.05 mole) of ethyl 4-bromophenylacetate with
9.6 g. (0.20 mole) of sodium hydride and reaction of the resulting
disodium salt with 28.4 g. (0.20 mole) of methyl iodide, the
product being purified by distillation in vacuo, gave 5.86 g. of
ethyl .alpha.-(4-bromophenyl).alpha.,.alpha.-dimethylpropionate,
b.p. 67.5.degree.-69.degree. C./0.04-0.045 mm.
Reduction of 22.83 g. (0.08 mole) of the latter with 4.78 g. (0.13
mole) of lithium aluminum hydride in 300 ml. of diethyl ether and
purification of the product by distillation in vacuo gave 17.1 g.
of 2,2-dimethyl-2-(4-bromophenyl)ethanol, b.p.
64.0.degree.-83.degree. C./0.05-0.075 mm. as a waxy solid.
Reaction of 87.37 g. (0.39 mole) of the latter with 64.5 g. (0.79
mole) of dihydropyran in the presence of 0.1 g. of
p-toluenesulfonic acid gave 117.3 g. of
2,2-dimethyl-2-(4-bromophenyl)ethanol tetrahydropyranyl ether.
Reaction of 117.3 g. (0.37 mole) of the latter with 0.49 mole of
n-butyl lithium in hexane in 187 ml. of anhydrous diethyl ether,
followed by reaction of the resulting lithium derivative with 55.3
g. (0.54 mole) of benzonitrile in 125 ml. of anhydrous diethyl
ether, followed by hydrolysis of the resulting imine and cleavage
of the pyranyl ether, the product being purified by distillation in
vacuo, gave 82.3 g. of 2,2-dimethyl-2-(4-benzoylphenyl)ethanol,
b.p. 165.degree.-183.degree. C./0.04-0.065 mm., n.sub.D.sup.25
=1.5950.
Reaction of 50.86 g. (0.2 mole) of the latter with 42.0 g. (0.22
mole) of p-toluenesulfonyl chloride in 100 ml. of pyridine and
purification of the product by recrystallization from cyclohexane
gave 62.8 g. of 2,2-dimethyl-2-(4-benzoylphenyl)ethanol
p-toluenesulfonate, m.p. 76.5.degree.-78.degree. C.
Reaction of 65 g. (0.16 mole) of the latter with 31.2 g. (0.36
mole) of morpholine in 60 ml. of N-methyl-2-pyrrolidinone and
isolation of the product in the form of the hydrochloride salt gave
7.7 g. of 4-[2,2-dimethyl-2-(4-benzoylphenyl)ethyl]morpholine
hydrochloride, m.p. 218.degree.-220.degree. C. (from acetone).
Example 24 L
Reaction of 14.3 g. (0.035 mole) of the latter with 43.1 g. (0.28
mole) of 1,4-dioxa-8-azaspiro[4,5]decane in 60 ml. of
N-methyl-2-pyrrolidinone and isolation of the product in the form
of the hydrochloride salt gave 7.16 g. of
8-[2,2-dimethyl-2-(4-benzoylphenyl)ethyl]-1,4-dioxa-8-azaspiro[4,5]decane
hydrochloride, m.p. 189.degree.-191.degree. C. (from acetone).
Example 24M
Reduction of .alpha.-(3-bromophenyl)propionaldehyde with sodium
borohydride using the procedure described in Example 3 and reaction
of the resulting 2-(3-bromophenyl)propanol with an excess of
dihydropyran at ambient temperature in the presence of a few drops
of concentrated hydrochloric acid affords 2-(3-bromophenyl)propane
tetrahydropyranyl ether. Reaction of the latter in diethyl ether
with n-butyl lithium followed by reaction of the resulting lithio
derivative with benzonitrile using the procedure described in
Example 7 affords 2-(3-benzoylphenyl)propanol which, on reaction
with p-toluenesulfonyl chloride in the presence of pyridine,
affords 2-(3-benzoylphenyl)propanol p-toluenesulfonate. Reaction of
the latter with 1-cyclohexylpiperazine in DMF in the presence of
anhydrous potassium carbonate affords
1-[2-(3-benzoylphenyl)propyl]-4-cyclohexylpiperazine.
EXAMPLE 25
A solution of 6.4 g. (0.015 mole) of
4-cyclohexyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride described above in Example 1E in 100 ml. of 85%
ethanol was placed in a Parr hydrogenator along with 1 g. of
palladium-on-charcoal and the mixture reduced at 56 p.s.i. and a
temperature of about 47.degree.-49.degree. C. When reduction was
complete, the catalyst was removed by filtration and washed with
ethanol, and the filtrate taken to dryness in vacuo. The crude
product (6.0 g., m.p. 212.degree.-215.degree. C.) was
recrystallized from acetone/diethyl ether to give 5.2 g. of
4-cyclohexyl-1-[.alpha.-(3-benzylphenyl)propionyl]piperazine
hydrochloride, m.p. 215.degree.-217.degree. C.
Following a procedure similar to that described in Example 25, the
following 3-[R.sub.1 -(phenyl)-CO]-phenyl-lower-alkanoylamines of
formula V were similarly prepared.
Example 25A
4-Cycloheptyl-1-[(3-benzylphenyl)acetyl]piperazine hydrochloride,
m.p. 245.degree.-248.degree. C. (4.57 g. from ethanol) prepared by
catalytic reduction of 5.95 g. (0.014 mole) of
4-cycloheptyl-1-[(3-benzoylphenyl)acetyl]piperazine described above
in Example 1M in 250 ml. of ethanol over 2.0 g. of
palladium-on-charcoal.
Example 25B
4-Cycloheptyl-1-[.alpha.-(3-benzylphenyl)propionyl]piperazine
hydrochloride, m.p. 186.degree.-187.degree. C. (7.45 g. from
acetone) prepared by catalytic reduction of 10.3 g. (0.023 mole) of
4-cycloheptyl-1-[.alpha.-(3-benzoylphenyl)propionyl]piperazine
hydrochloride described above in Example 1K in 250 ml. of ethanol
over 1.5 g. of palladium-on-charcoal.
EXAMPLE 26
It is contemplated that, by following procedures similar to those
described in Examples 24A-24M, reaction of 2-bromoacetophenone with
sodium isopropoxide and ethyl chloroacetate would afford ethyl
2-methyl-2-(2-bromophenyl)glycidate.
Saponification of the latter with alkali would afford
.alpha.-(2-bromophenyl)propionaldehyde.
Reduction of the latter with sodium borohydride in methanol would
afford 2-(2-bromophenyl)propanol.
Reaction of the latter with dihydropyran in the presence of a trace
of concentrated hydrochloric acid would afford
2-(2-bromophenyl)propanol tetrahydropyranyl ether.
Reaction of the latter with a molar equivalent amount of n-butyl
lithium followed by reaction of the resulting lithium derivative
with benzonitrile, hydrolysis of the resulting imine and cleavage
of the pyranyl ether function would afford
2-(2-benzoylphenyl)propanol.
Reaction of the latter with p-toluenesulfonyl chloride in pyridine
would afford 2-(2-benzoylphenyl)propyl p-toluenesulfonate.
Reaction of the latter with two molar equivalents of (A)
piperidine; (B) 2-cyclohexylmethylpiperidine; (C)
2,6-dimethylpiperidine; (D) 2-(3-cyclohexylpropyl)piperidine; (E)
2-cyclohexylmethylpyrrolidine; (F) 2-cyclohexylpiperidine; (G)
2-(2-cyclohexylethyl)piperidine; (H) morpholine; (J)
thiomorpholine; (K) 2,6-dimethylmorpholine; (L)
1,4-dioxa-8-azaspiro[4,5]decane; (M)
1-oxa-4-thia-8-azaspiro[4,5]decane; or (N)
1,4-dithia-8-azaspiro[4,5]decane would afford, respectively:
(A) 1-[2-(2-benzoylphenyl)propyl]piperidine;
(B) 2-cyclohexylmethyl-1-[2-(2-benzoylphenyl)propyl]piperidine;
(C) 2,6-dimethyl-1-[2-(2-benzoylphenyl)propyl]piperidine;
2-(3-cyclohexylpropyl)-1-[2-(2-benzoylphenyl)propyl]piperidine;
(E)
2-cyclohexylmethyl-1-[2-(2-benzoylphenyl)propyl]pyrrolidine;
(F) 2-cyclohexyl-1-[2-(2-benzoylphenyl)propyl]piperidine;
(G)
2-(2-cyclohexylethyl)-1-[2-(2-benzoylphenyl)propyl]piperidine;
(H) 4-[2-(2-benzoylphenyl)propyl]morpholine;
(J) 4-[2-(2-benzoylphenyl)propyl]thiomorpholine;
(K) 2,6-dimethyl-4-[2-(2-benzoylphenyl)propyl]morpholine;
(L)
8-[2-(2-benzoylphenyl)propyl]-1,4-dioxa-8-azaspiro[4,5]decane;
(M)
8-[2-(2-benzoylphenyl)propyl]-1-oxa-4-thia-8-azaspiro[4,5]decane;
or
(N)
8-[2-(2-benzoylphenyl)propyl]-1,4-dithia-8-azaspiro[4,5]decane.
BIOLOGICAL TEST RESULTS
The N-{2-,3- and 4-[R.sub.1
-(phenyl)-C(.dbd.X)]-phenyllower-alkyl}amines of formulas I, Ia and
Ib of the invention have been tested in the carrageenin edema (CE)
and adjuvant arthritis (AA) tests and found to have
anti-inflammatory activity. Data so obtained, stated in terms of
percent inhibition at a dose expressed in terms of millimoles/kg.,
are given in TABLE A below. For comparative purposes, data obtained
in the carrageenin edema test on the reference compound (designated
"Ref."), 4[(3-benzoylphenyl)methyl]morpholine, disclosed in French
Patent 1,549,342, are also given. All data were obtained on oral
administration.
TABLE A ______________________________________ Example Dose C.E.
A.A. ______________________________________ 1 0.005 13 56** 0.02 23
73** 0.08 60** 91** 0.324 73** -- 1A 0.004 0 -- 0.02 0 -- 0.08 51**
-- 0.324 62** -- 1B 0.004 0 -- 0.02 0 -- 0.08 13 -- 0.324 Toxic --
1C 0.08 40* -- 0.324 77** -- 1D 0.08 36* -- 0.324 65* -- 3 0.005 0
0 0.02 3 2 0.08 35* 30 3A 0.004 0 -- 0.02 0 -- 0.08 34** -- 0.324
75** -- 3B 0.08 19 -- 0.16 -- 91** 0.324 63** -- 3E 0.004 14 --
0.02 34** -- 4 0.004 0 -- 0.02 1 -- 0.08 18 -- 0.324 72** -- 5
0.004 14 -- 0.005 -- 64** 0.02 41* 70** 0.08 -- 88** 5A 0.004 0 --
0.02 0 -- 0.08 58* -- 0.324 68** -- 6 0.004 14 -- 0.02 5 -- 0.08
28* -- 0.324 55** -- 7 0.004 0 -- 0.02 22 -- 0.08 -- 63** 7A 0.08
45** -- 0.16 -- 90** 0.324 60** -- 7B 0.004 3 -- 0.005 -- 61** 0.02
38* 55* 0.08 -- 85* 7C 0.004 0 -- 0.02 10 -- 0.08 58** -- 0.324
75** -- 7D 0.08 37** -- 0.16 -- 100** 0.324 49** -- 7E 0.08 33*
92** 0.324 58** 7F 0.08 33** 91** 0.16 -- Toxic 0.324 51** --
7G(base) 0.004 33** -- 0.02 42** -- 0.08 -- 76** 7H(base) 0.004 29*
-- 0.02 44** -- 0.08 -- 81** 7H(HCl) 0.08 68* -- 0.324 73** -- 7J
0.08 62** -- 0.324 66** -- 8 0.004 2 -- 0.02 21 -- 0.08 33** --
0.324 68** -- 9 0.004 0 -- 0.02 0 -- 0.08 21 -- 0.324 47** -- 10
0.005 7 25 0.02 26* 63* 0.08 60** 91** 11 0.004 0 -- 0.02 15 --
0.08 29* -- 0.324 64** -- 12,14 0.005 21 69** 0.02 41** 81** 0.08
51** 87** 0.324 69** -- 13 0.004 0 37** 0.015 15 52** 0.06 37* 78**
0.08 54** -- 0.324 56** -- 14(a) 0.0013 -- 16(28**)[0] 0.005 --
46**(46**)[39*] 0.02 -- 79**(87**)[65**] 14A 0.08 39** 49* 0.324
67** 15 0.004 16 -- 0.02 43** 92** 0.08 91** 15A 0.08 27 -- 0.324
29 -- 16 0.004 16 -- 0.005 -- 80** 0.02 31* 89** 0.08 -- 108** 16A
0.08 27 -- 0.324 39* -- 16B 0.08 0 -- 0.324 36* 0 16C 0.08 49** --
0.324 84** -- 17 0.004 9 -- 0.02 16 -- 0.08 47** -- 0.324 67** --
19 0.02 5 -- 0.08 0 -- 0.16 -- 1 0.324 23* -- 20 0.004 16 -- 0.005
-- 63** 0.02 52** 90** 0.08 -- Toxic 20A 0.04 9 -- 0.02 25 -- 0.08
46** -- 0.324 70** -- 20B 0.004 14 -- 0.02 0 -- 0.08 22* -- 0.324
65** -- 20C 0.004 17* -- 0.02 15 -- 0.08 19* -- 0.324 51** -- 20D
0.004 0 -- 0.005 -- 35* 0.02 36** 54* 0.08 -- 79** 21 0.08 32 --
0.324 46** -- 22 0.08 29 -- 0.324 63** -- 24A 0.08 44** 0.324 56**
78** 24B 0.08 38* 30 0.324 50** Toxic 24C 0.08 16 0.324 41** 63**
24D 0.08 61** 28** 0.324 70** 24G 0.08 32** 0.324 52** 24H 0.08 0
0.324 22 8 24J 0.08 6 0.324 8 36** 24K 0.08 19 0.324 60** 7 24L
0.08 46** 24 0.324 70** Ref. 0.08 0 -- 0.324 23* --
______________________________________ *Statistically different
from controls p. .ltoreq..05 **Statistically different from
controls p. .ltoreq..01 (a)The diastereoisomer of the compound of
Example 12. (b)The numbers in parentheses represent results
obtained in a second experiment, the numbers in brackets the the
results obtained on administering the test compound in a corn oil
vehicle.
The N-{3-[R.sub.1 -(phenyl)-C(.dbd.X)]-phenyl-lower-alkanoyl}amines
of formula V have also been tested in the carrageenin edema and
adjuvant arthritis tests and found to have antiinflammatory
activity. Data so obtained, expressed as in Table A above, are
given in Table B below.
TABLE B ______________________________________ Example Dose C.E.
A.A. ______________________________________ 1 0.08 21* -- 0.324
36**(a) 67**(a) 1E 0.08 10 63** 0.324 61**(b) -- 1F 0.08 2 -- 0.324
18 58* 1J 0.08 18 -- 0.324 72** -- 1L 0.08 13 -- 0.324 31**(a)
74**(a) 25 0.08 0 -- 0.162 -- 79** 0.324 45** -- 25B 0.08 25* --
0.324 44** 78** ______________________________________
(a)Insufficient compound to medicate for entire 21 day period of
standard test. Data obtained after 17 days on test and 9
medications. (b)Convulsions and salivation produced in 2 of 8 test
animals.
Certain of the N-{3- and 4-[R.sub.1
-(phenyl)-C(.dbd.X)]-phenyl-lower-alkyl}amines of formula I of the
invention have been found to have analgesic activity as determined
in the acetylcholine-induced abdominal constriction test (Ach), the
anti-bradykinin test (BDK), the phenyl-p-quinone induced writhing
test (PPQ), the rat tail flick agonist test (T.F.Ag.) and/or the
rat tail flick antagonist test (T.F. Antag.). Data so obtained for
the species found active in one or more of these tests are given in
TABLE C below, results being expressed either in terms of the
ED.sub.50 or, in the acetylcholine-induced writhing test, as the
percent inhibition of writhing in the test animals at a given dose
level. The ED.sub.50 is the calculated Effective Dose in 50% of the
test animals. The abbreviations s.c., p.o. and i.p. stand for
subcutaneous, peroral and intraperitoneal routes of administration,
respectively. The compounds are identified by the Example numbers
above where their preparations are described.
TABLE C ______________________________________ T.F. T.F. Example
Ach BDK PPQ Ag. Antag. ______________________________________ 1 71
(p.o.) -- -- -- -- 33%/75 (s.c.) 7%/25 (s.c.) 7E 93%/75 (s.c.) --
-- -- -- 46%/25 (s.c.) 7F 33%/75 (s.c.) -- -- -- -- 7%/25 (s.c.)
7G(a) 4.7 (p.o) 14 (p.o) 200 (p.o.) Inac. Inac. 7H(HCl)(b) 14
(s.c.) 13 (p.o.) 132 (p.o.) Inac. Inac. 8.4 (p.o.) 82 (i.p.) 55
(p.o.) 63 (p.o.) -- -- -- 12,14 27%/75 (s.c.) 24A 13%/25 (s.c.) 19
(p.o.) -- -- -- -- 24C 20 (p.o.) -- -- -- -- 24D 50 (p.o.) -- -- --
-- 24E 39 (p.o.) -- -- -- -- 24F 18 (p.o.) -- -- -- -- 24G 30
(p.o.) -- -- -- -- 5.6 (s.c.) 24H 73%/150 (s.c.) -- -- -- -- 13%/50
(s.c.) 7%/25 (s.c.) 24J 53%/150 (p.o.) -- -- -- -- 27%/50 (p.o.)
33%/25 (s.c.) 24K 38 (p.o.) -- -- -- -- 24L 60 (p.o.) -- -- -- --
______________________________________ (a)Showed significant
antipyretic activity in the rat at 26 and 13 mg./kg (p.o.) but not
at 6.5 or 3.25 mg./kg. (p.o.). (b)Showed significant antipyretic
activity in the rat at 26, 13 and 6.5 mg./kg. (p.o.) but not at
3.25 mg./kg. (p.o.).
Certain of the N-{3-[R.sub.1
-(phenyl)-C(.dbd.X)]-phenyl-lower-alkyl}amines of formula I of the
invention have been tested for anti-viral activity against herpes
simplex virus types 1 and 2 and have been found to have anti-viral
activity. Data so-obtained expressed in terms of the Minimum
Inhibitory Concentration (mcg./ml.), are given in TABLE D
below.
TABLE D ______________________________________ Example MIC
______________________________________ 1B 50 mcg./ml. 5 6 mcg./ml.
10 6 mcg./ml. 12,14 6 mcg./ml.
______________________________________
* * * * *